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Safety, tolerability, and pharmacokinetics of AZD5462, a small molecule agonist of the RXFP1 relaxin receptor

医学 耐受性 安慰剂 不利影响 药代动力学 随机对照试验 沙库比林 内科学 队列 托尔瓦普坦 药理学 缬沙坦 心力衰竭 血压 替代医学 病理
作者
Jaya B. Rosenmeier,Katherine Connolly,Elin M. Matsson,Magnus Åstrand,Magnus Althage,Daniel Pettersen,Alexandra L. Whittaker,Michael Turton,Mirjana Kujacic,A E Gabrielsen
出处
期刊:European Heart Journal [Oxford University Press]
卷期号:44 (Supplement_2) 被引量:1
标识
DOI:10.1093/eurheartj/ehad655.976
摘要

Abstract Introduction Despite multiple new drug advancements for patients with heart failure in recent years (specifically, sodium-glucose co-transporter-2 and sacubitril/valsartan), morbidity and mortality remain high. AZD5462 is a selective RXFP1 agonist which mimics the pregnancy hormone relaxin and its actions on systemic hemodynamics and kidney function. Purpose To assess the safety, tolerability, and pharmacokinetics (PK) of AZD5462 in a first-in-human study following single ascending dose (SAD) and multiple ascending dose (MAD) administration in healthy participants. Methods This was a phase 1 randomized, double-blind, placebo-controlled study. The SAD evaluated doses of 20, 80, 400, 750, and 1000 mg across 7 cohorts, with 2 cohorts comprising solely participants of Japanese descent. The MAD evaluated doses of 40, 120, 250, and 500 mg BID for 10 days across 5 cohorts, with 1 cohort of Japanese descent. There were approximately 8 participants in each cohort, randomized 6:2 to AZD5462 or placebo. AZD5462 was administered as an oral liquid solution. Results Overall, 98 participants were randomized and 92 completed the study (56 of 56 in SAD; 36 of 42 in MAD). The majority of participants randomized were male, and the median age was 39 years in the SAD and 36 years in the MAD. There were no major safety and tolerability concerns up to the highest dose administered (1000 mg SAD; 500 mg BID MAD). Pre-specified study stopping criteria were not met. There were no deaths or other serious adverse events. AEs were more common in the pooled AZD5462 group than placebo (approximately 40% for AZD5462 and 20% for placebo). The most common AEs were GI disorders (nausea, abdominal pain, vomiting), headache, medical device site dermatitis, and orthostatic heart rate response increase, but without clear relationship to dose. Three participants discontinued the MAD due to dizziness, supraventricular tachycardia, and positive COVID-19 test. There was no clear pattern in the effect on SBP with 120 mg and higher doses in the MAD. There was a trend for DBP decrease but no signs of hypotension. HR increased in all cohorts, which was dose-dependent in SAD but without clear relationship to dose in MAD. Treatment with AZD5462 led to a dose-dependent increase in plasma renin in all but the lowest SAD dose. AZD5462 was rapidly absorbed with a median Tmax between 0.53 hr and 1.75 hr. Plasma concentrations declined in a biphasic manner, with a geometric mean terminal half-life after a single dose between 3 h and 6 h. The exposure to AZD5462 increased more than proportionately with dose. Conclusions AZD5462 was generally well tolerated at all dose levels in this phase 1 study. These data pave the way for development of a chronic oral relaxin therapy for patients with heart failure.
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