Abstract：
BACKGROUND: Heart failure mortality remains high despite recent progress in pharmacological treatment. AZD3427 is a selective long-acting analog of relaxin, a vasodilatory hormone with antifibrotic effects. We assessed the safety, pharmacokinetics, and pharmacodynamics of AZD3427 in healthy volunteers and patients with heart failure on standard-of-care therapy.
RESULTS: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected.
CONCLUSIONS: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure.
BACKGROUND: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.
RESULTS: In this first-in-human, phase 1a/b, randomized, single-blind, placebo-controlled study, healthy volunteers were randomized 6:2 to receive a single dose of AZD3427 or placebo by subcutaneous injection in 5 mixed-ethnicity cohorts (5, 10, 30, 90, or 270 mg) and 1 Japanese-descent cohort (270 mg), or by intravenous injection in 1 cohort (15 mg). After confirming safety and tolerability in healthy volunteers, 3 cohorts of patients with heart failure and left ventricular ejection fraction ≤40% and 3 cohorts with ejection fraction ≥41% were randomized 6:2 to receive 5 weekly doses of AZD3427 (5, 15, or 45 mg) or placebo by subcutaneous injection. In total, 56 healthy volunteers and 48 patients with heart failure were randomized. AZD3427 was well tolerated at all doses. After subcutaneous administration, AZD3427 was absorbed slowly, and exposure was approximately linear across the dose range. In patients with heart failure, AZD3427 terminal half-life was 13 to 14 days and there were numerical increases in stroke volume and estimated glomerular filtration rate. No treatment-emergent antidrug antibodies were detected.
CONCLUSIONS: AZD3427 had favorable safety and pharmacokinetic profiles. Hemodynamic changes in patients with heart failure were consistent with the anticipated effects of a relaxin analog. These findings support further development of AZD3427 as a novel long-term treatment for patients with heart failure.
BACKGROUND: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.
摘要：
背景：尽管药物治疗最近取得了进展，但心力衰竭死亡率仍然很高。AZD3427是松弛素的选择性长效类似物，一种具有抗纤维化作用的血管舒张激素。我们评估了安全性,药代动力学，AZD3427在健康志愿者和标准治疗心力衰竭患者中的药效学。
结果：在这个人类第一，阶段1a/b，随机化，单盲,安慰剂对照研究，健康志愿者被随机分为6:2，分别在5个混合种族队列（5、10、30、90或270mg）和1个日本裔队列（270mg）中接受皮下注射的单剂量AZD3427或安慰剂，或通过静脉注射1组（15毫克）。在确认健康志愿者的安全性和耐受性后，将3组心力衰竭且左心室射血分数≤40％的患者和3组射血分数≥41％的患者随机分为6：2，接受5次每周剂量的AZD3427（5、15或45mg）或安慰剂皮下注射。总的来说,将56名健康志愿者和48名心力衰竭患者随机分组。AZD3427在所有剂量下都具有良好的耐受性。皮下给药后，AZD3427吸收缓慢，和暴露在整个剂量范围内大致呈线性。心力衰竭患者,AZD3427终末半衰期为13至14天，并且每搏量和估计的肾小球滤过率都有增加。未检测到治疗时出现的抗药物抗体。
结论：AZD3427具有良好的安全性和药代动力学特征。心力衰竭患者的血液动力学变化与松弛素类似物的预期效果一致。这些发现支持AZD3427作为心力衰竭患者的新型长期治疗方法的进一步发展。
背景：URL：https://www。clinicaltrials.gov；唯一标识符：NCT04630067。
结果：在这个人类第一，阶段1a/b，随机化，单盲,安慰剂对照研究，健康志愿者被随机分为6:2，分别在5个混合种族队列（5、10、30、90或270mg）和1个日本裔队列（270mg）中接受皮下注射的单剂量AZD3427或安慰剂，或通过静脉注射1组（15毫克）。在确认健康志愿者的安全性和耐受性后，将3组心力衰竭且左心室射血分数≤40％的患者和3组射血分数≥41％的患者随机分为6：2，接受5次每周剂量的AZD3427（5、15或45mg）或安慰剂皮下注射。总的来说,将56名健康志愿者和48名心力衰竭患者随机分组。AZD3427在所有剂量下都具有良好的耐受性。皮下给药后，AZD3427吸收缓慢，和暴露在整个剂量范围内大致呈线性。心力衰竭患者,AZD3427终末半衰期为13至14天，并且每搏量和估计的肾小球滤过率都有增加。未检测到治疗时出现的抗药物抗体。
结论：AZD3427具有良好的安全性和药代动力学特征。心力衰竭患者的血液动力学变化与松弛素类似物的预期效果一致。这些发现支持AZD3427作为心力衰竭患者的新型长期治疗方法的进一步发展。
背景：URL：https://www。clinicaltrials.gov；唯一标识符：NCT04630067。
