Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, 4070, Basel, Switzerland.
Regul Toxicol Pharmacol. 2023 Jun;141:105407. doi: 10.1016/j.yrtph.2023.105407. Epub 2023 May 2.
The non-clinical safety profile of the small molecule hepatitis B virus viral expression inhibitor RG7834 was studied in a package consisting of safety pharmacology, genotoxicity, repeat dose toxicity and reproductive toxicity studies. The chronic monkey toxicity study identified dose- and time-dependent symptoms of polyneuropathy, with correlating nerve conduction velocity reductions and axonal degeneration in peripheral nerves and spinal cord, in all compound treatment groups with no evidence of reversibility after approximately 3 months of treatment cessation. Similar histopathological findings were observed in the chronic rat toxicity study. Subsequent in vitro neurotoxicity investigations and ion channel electrophysiology did not elucidate a potential mechanism for the late toxicity. However, based on similar findings observed with a structurally different molecule, an inhibition of their common pharmacological targets, PAPD5 & PAPD 7, was considered as a possible mechanism of toxicity. In conclusion, the marked neuropathies, only observed after chronic dosing, did not support further clinical development of RG7834 because of its foreseen clinical treatment duration of up to 48 weeks in chronic HBV patients.
小分子乙型肝炎病毒病毒表达抑制剂 RG7834 的非临床安全性特征在一个包含安全性药理学、遗传毒性、重复剂量毒性和生殖毒性研究的研究包中进行了研究。慢性猴子毒性研究发现，所有化合物治疗组均存在与剂量和时间相关的多发性神经病症状，伴有周围神经和脊髓神经传导速度降低和轴突变性，在大约 3 个月的停药后没有可逆证据。在慢性大鼠毒性研究中也观察到了类似的组织病理学发现。随后的体外神经毒性研究和离子通道电生理学研究未能阐明潜在的毒性机制。然而，基于与结构不同的分子观察到的类似发现，抑制其共同的药理靶点 PAPD5 和 PAPD7 被认为是一种可能的毒性机制。总之，只有在慢性给药后才观察到的明显神经病变，由于其在慢性 HBV 患者中的临床治疗持续时间长达 48 周，不支持 RG7834 的进一步临床开发。
