Korolowizc Kyle E, Li Bin, Huang Xu, Yon Changsuek, Rodrigo Evelyn, Corpuz Manny, Plouffe David M, Kallakury Bhaskar V, Suresh Manasa, Wu Tom Y-H, Miller Andrew T, Menne Stephan
Department of Microbiology and Immunology Georgetown University Medical Center Washington DC.
Apros Therapeutics, Inc. San Diego CA.
Hepatol Commun. 2019 Jul 8;3(10):1296-1310. doi: 10.1002/hep4.1397. eCollection 2019 Oct.
Current therapeutics for chronic infection with hepatitis B virus (HBV) rarely induce functional cure due to the immunotolerant status of patients. Small molecule agonists targeting toll-like receptor 7 (TLR7) have been shown to elicit a functional cure in animal models of HBV but sometimes with poor tolerability due to immune-related toxicities. In an effort to increase the therapeutic window of TLR7 agonists to treat chronic hepatitis B (CHB), we developed an oral TLR7 agonist, APR002, designed to act locally in the gastrointestinal tract and liver, thus minimizing systemic exposure and improving tolerability. Here, we describe the pharmacokinetic/pharmacodynamic (PK/PD) profile of APR002 in mice and uninfected woodchucks as well as the safety and antiviral efficacy in combination with entecavir (ETV) in woodchucks with CHB. Treatment of woodchucks chronically infected with woodchuck hepatitis virus (WHV) with weekly oral doses of APR002 was well-tolerated. While APR002 and ETV single agents did not elicit sustained viral control, combination therapy resulted in durable immune-mediated suppression of the chronic infection. These woodchucks also had detectable antibodies to viral antigens, enhanced interferon-stimulated gene expression, and loss of WHV covalently closed circular DNA. APR002 is a novel TLR7 agonist exhibiting a distinct PK/PD profile that in combination with ETV can safely attain a functional cure in woodchucks with chronic WHV infection. Our results support further investigation of liver-targeted TLR7 agonists in human CHB.
由于患者的免疫耐受状态，目前用于慢性乙型肝炎病毒（HBV）感染的治疗方法很少能实现功能性治愈。靶向Toll样受体7（TLR7）的小分子激动剂已被证明在HBV动物模型中能引发功能性治愈，但有时由于免疫相关毒性而耐受性较差。为了扩大TLR7激动剂治疗慢性乙型肝炎（CHB）的治疗窗口，我们开发了一种口服TLR7激动剂APR002，其设计目的是在胃肠道和肝脏中局部发挥作用，从而最大限度地减少全身暴露并提高耐受性。在此，我们描述了APR002在小鼠和未感染土拨鼠中的药代动力学/药效学（PK/PD）特征，以及与恩替卡韦（ETV）联合使用对慢性乙型肝炎土拨鼠的安全性和抗病毒疗效。每周口服APR002治疗慢性感染土拨鼠肝炎病毒（WHV）的土拨鼠耐受性良好。虽然APR002和ETV单药治疗未能实现持续的病毒控制，但联合治疗导致了对慢性感染的持久免疫介导抑制。这些土拨鼠还检测到了针对病毒抗原的抗体，干扰素刺激基因表达增强，并且WHV共价闭合环状DNA消失。APR002是一种新型TLR7激动剂，具有独特的PK/PD特征，与ETV联合使用可安全地使慢性WHV感染的土拨鼠实现功能性治愈。我们的结果支持进一步研究肝脏靶向TLR7激动剂在人类慢性乙型肝炎中的应用。
