Early Clinical Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D AstraZeneca Cambridge UK.
Development, Research and Early Development, Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D AstraZeneca Gaithersburg MD.
J Am Heart Assoc. 2024 Aug 6;13(15):e034067. doi: 10.1161/JAHA.123.034067. Epub 2024 Jul 26.
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.
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.
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.
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04630067.
尽管在药物治疗方面最近取得了进展，但心力衰竭的死亡率仍然很高。AZD3427 是松弛素的一种选择性长效类似物，松弛素是一种具有抗纤维化作用的血管舒张激素。我们评估了 AZD3427 在接受标准治疗的健康志愿者和心力衰竭患者中的安全性、药代动力学和药效学。
在这项首次人体、1a/b 期、随机、单盲、安慰剂对照研究中，健康志愿者按 6:2 的比例随机接受皮下注射单剂量 AZD3427 或安慰剂，分为 5 个混合种族队列（5、10、30、90 或 270mg）和 1 个日本裔队列（270mg），或静脉注射 1 个队列（15mg）。在健康志愿者中确认安全性和耐受性后，将 3 个心力衰竭且左心室射血分数≤40%的队列和 3 个射血分数≥41%的队列按 6:2 的比例随机分为 5 组，接受皮下注射 5 周 AZD3427（5、15 或 45mg）或安慰剂。总共 56 名健康志愿者和 48 名心力衰竭患者被随机分组。在所有剂量下，AZD3427 均具有良好的耐受性。皮下给药后，AZD3427 吸收缓慢，暴露量在剂量范围内呈近似线性。在心衰患者中，AZD3427 的终末半衰期为 13 至 14 天，并且每搏量和估算肾小球滤过率均有数值增加。未检测到治疗引起的抗药抗体。
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作用一致。这些发现支持进一步开发 AZD3427 作为心力衰竭患者的新型长期治疗方法。
