Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
Covance Phase 1 Unit, Dallas, Texas.
Diabetes Obes Metab. 2018 Feb;20(2):283-291. doi: 10.1111/dom.13075. Epub 2017 Sep 14.
Glucagon receptor (GCGR) blockers are being investigated as potential therapeutics for type 1 and type 2 diabetes. Here we report the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of REGN1193, a fully human glucagon receptor blocking monoclonal antibody from a first-in-human healthy volunteer randomized double-blinded trial.
Healthy men and women received single ascending doses of REGN1193 ranging from 0.05 to 0.6 mg/kg (n = 42) or placebo (n = 14) intravenously. Safety, tolerability and PK were assessed over 106 days. The glucose-lowering effect of REGN1193 was assessed after induction of hyperglycaemia by serial glucagon challenges.
REGN1193 was generally well tolerated. There were small (<3× the upper limit of normal) and transient dose-dependent increases in hepatic aminotransferases. No increase in LDL-C was observed. Hypoglycaemia, assessed as laboratory blood glucose ≤70 mg/dL, occurred in 6/14 (43%) subjects on placebo and 27/42 (57%) on REGN1193 across all dose groups. All episodes of hypoglycaemia were asymptomatic, >50 mg/dL, and did not require treatment or medical assistance. Concentration-time profiles suggest a 2-compartment disposition and marked nonlinearity, consistent with target-mediated clearance. REGN1193 inhibited the glucagon-stimulated glucose increase in a dose-dependent manner. The 0.6 mg/kg dose inhibited the glucagon-induced glucose area under the curve for 0 to 90 minutes (AUC ) by 80% to 90% on days 3 and 15, while blunting the increase in C-peptide. REGN1193 dose-dependently increased total GLP-1, GLP-2 and glucagon, with plasma levels returning to baseline by day 29 in all dose groups.
REGN1193, a GCGR-blocking monoclonal antibody, produced a safety, tolerability and PK/PD profile suitable for further clinical development. The occurrence of transient elevations in serum hepatic aminotransferases observed here and reported with several small molecule glucagon receptor antagonists suggests an on-target effect of glucagon receptor blockade. The underlying mechanism is unknown.
胰高血糖素受体（GCGR）阻断剂正在被研究作为 1 型和 2 型糖尿病的潜在治疗方法。在这里，我们报告了 REGN1193 的安全性、耐受性、药代动力学（PK）和药效学（PD），REGN1193 是一种来自首次人体健康志愿者随机双盲试验的全人源胰高血糖素受体阻断单克隆抗体。
健康男性和女性接受了静脉注射的单剂量递增的 REGN1193 剂量范围为 0.05 至 0.6mg/kg（n=42）或安慰剂（n=14）。在 106 天内评估安全性、耐受性和 PK。通过连续给予胰高血糖素挑战诱导高血糖来评估 REGN1193 的降血糖作用。
REGN1193 通常具有良好的耐受性。有小的（<3×正常上限）且短暂的剂量依赖性肝转氨酶升高。未观察到 LDL-C 升高。在安慰剂组中，有 6/14（43%）的受试者和 REGN1193 所有剂量组中 27/42（57%）的受试者出现实验室血糖≤70mg/dL 的低血糖。所有低血糖发作均无症状，>50mg/dL，无需治疗或医疗救助。浓度-时间曲线表明存在 2 隔室分布和明显的非线性，与靶介导清除一致。REGN1193 以剂量依赖性方式抑制胰高血糖素刺激的葡萄糖增加。在第 3 天和第 15 天，0.6mg/kg 剂量抑制胰高血糖素诱导的葡萄糖 0 至 90 分钟 AUC 减少 80%至 90%，同时减弱 C-肽的增加。REGN1193 剂量依赖性地增加总 GLP-1、GLP-2 和胰高血糖素，所有剂量组的血浆水平在 29 天内均恢复到基线。
REGN1193 是一种 GCGR 阻断单克隆抗体，其安全性、耐受性和 PK/PD 特征适合进一步的临床开发。在此处观察到并与几种小分子胰高血糖素受体拮抗剂报告的血清肝转氨酶短暂升高表明胰高血糖素受体阻断的靶标效应。其潜在机制尚不清楚。
