Nonclinical Safety, Bristol-Myers Squibb, New Brunswick, NJ, USA.
Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Princeton, NJ, USA.
Toxicol Appl Pharmacol. 2022 Mar 1;438:115846. doi: 10.1016/j.taap.2021.115846. Epub 2021 Dec 31.
BMS-986020, BMS-986234 and BMS-986278, are three lysophosphatidic acid receptor 1 (LPA) antagonists that were or are being investigated for treatment of idiopathic pulmonary fibrosis (IPF). Hepatobiliary toxicity (elevated serum AST, ALT, and ALP, plasma bile acids [BAs], and cholecystitis) was observed in a Phase 2 clinical trial with BMS-986020, and development was discontinued. In dogs and rats, the species used for the pivotal toxicology studies, there was no evidence of hepatobiliary toxicity in the dog while findings in the rat were limited to increased plasma BAs levels (6.1× control), ALT (2.9×) and bilirubin (3.4×) with no histopathologic correlates. Since neither rats nor dogs predicted clinical toxicity, follow-up studies in cynomolgus monkeys revealed hepatobiliary toxicity that included increased ALT (2.0× control) and GLDH (4.9×), bile duct hyperplasia, cholangitis, cholestasis, and cholecystitis at clinically relevant BMS-986020 exposures with no changes in plasma or liver BAs. This confirmed monkey as a relevant species for identifying hepatobiliary toxicity with BMS-986020. In order to assess whether the toxicity was compound-specific or related to LPA antagonism, two structurally distinct LPA antagonists (BMS-986234 and BMS-986278), were evaluated in rat and monkey. There were no clinical or anatomic pathology changes indicative of hepatobiliary toxicity. Mixed effects on plasma BAs in both rat and monkey has made this biomarker not a useful predictor of the hepatobiliary toxicity. In conclusion, the nonclinical data indicate the hepatobiliary toxicity observed clinically and in monkeys administered BMS-986020 is compound specific and not mediated via antagonism of LPA.
BMS-986020、BMS-986234 和 BMS-986278 是三种溶血磷脂酸受体 1（LPA）拮抗剂，曾被用于或正在被用于特发性肺纤维化（IPF）的治疗。在 BMS-986020 的一项 2 期临床试验中观察到了肝胆毒性（血清 AST、ALT 和 ALP 升高、血浆胆汁酸[BAs]升高和胆囊炎），随后停止了开发。在犬和大鼠中，这两种物种被用于关键性毒理学研究，在犬中没有发现肝胆毒性的证据，而在大鼠中的发现仅限于血浆 BAs 水平升高（对照的 6.1 倍）、ALT（对照的 2.9 倍）和胆红素（对照的 3.4 倍），但没有组织病理学相关性。由于大鼠和犬均不能预测临床毒性，随后在食蟹猴中的研究揭示了肝胆毒性，包括 ALT（对照的 2.0 倍）和 GLDH（对照的 4.9 倍）升高、胆管增生、胆管炎、胆汁淤积和胆囊炎，同时 BMS-986020 的暴露水平与血浆或肝脏 BAs 无关。这证实了猴子是识别 BMS-986020 肝胆毒性的相关物种。为了评估毒性是否是化合物特异性的或与 LPA 拮抗作用相关，两种结构不同的 LPA 拮抗剂（BMS-986234 和 BMS-986278）在大鼠和猴中进行了评估。没有临床或解剖病理学变化提示肝胆毒性。在大鼠和猴中，血浆 BAs 的混合效应使得该生物标志物不能作为肝胆毒性的有用预测指标。总之，非临床数据表明，在给予 BMS-986020 的临床和猴子中观察到的肝胆毒性是化合物特异性的，而不是通过拮抗 LPA 介导的。
