Safety and Efficacy Testing of FX101 in an SIV/NHP Model

摘要 虽然高效抗逆转录病毒疗法（HAART）显著改善了感染者的健康， 对于人类免疫缺陷病毒-1（HIV），现有的治疗方法主要针对病毒复制途径 使得治疗中断导致病毒复制的快速恢复和免疫功能的下降， 功能尽管成功地控制了复制、慢性炎症、HIV相关性 神经认知障碍、心血管疾病和其他合并症进一步威胁着老年人的健康。 美国估计有120万艾滋病毒感染者。 抑制和减少持续性病毒的来源将减轻每日药物治疗的后果。 全球超过3400万艾滋病毒感染者的依从性和合并症。 Jericho Sciences的研究性小分子FX 101被提议靶向高度保守的锌指 结构域的慢病毒核衣壳（NC）蛋白，一个完善的治疗目标，用于治疗艾滋病毒。 FX 101已在多种体内、离体和体外模型中证明了临床前安全性和抗病毒疗效 以支持持续的翻译测试。HIV核衣壳（NC）蛋白的锌指结构域（ZFD）是一个重要的蛋白质结构域。 所有慢病毒（包括猫、猿和人）共有的高度保守的治疗靶点 免疫缺陷病毒（分别为FIV、SIV和HIV）。FX 101单次给药8次后 在慢性FIV感染的猫-HIV的研究模型之一-血浆和 脑脊液病毒血症保持85-95%低于相应的治疗前水平，长达36周 停止治疗后，在没有观察到或测量到的不良事件的情况下（p<0.0005; n=6; 单因素方差分析）。这些结果在FIV感染的猫中是前所未有的。同时，整合的前病毒在 外周血单个核细胞从标准化的起始病毒载量继续下降95 （p<0.0001; n=6;单因素方差分析）。虽然我们还没有完全阐明机械的影响， 核衣壳靶谱，最有区别的特征是潜在的长期控制病毒生产 在病毒复制设定点的明显系统性降低中。我们建议在这里进行翻译测试 在猴免疫缺陷病毒感染的非人灵长类动物（SIV/NHP）模型中， 安全性特征、治疗疗效和可能涉及该战略候选药物的临床生物标志物 分子的潜在效用对共同治疗功能根除人类HIV感染。 .

Abstract While highly active antiretroviral therapy (HAART) has significantly improved the health of individuals infected with human immunodeficiency virus-1 (HIV), available therapeutics largely target virus replication pathways such that treatment interruption results in the rapid resumption of viral replication and decline of immunologic function. Even despite successful therapeutic control of replication, chronic inflammation, HIV-associated neurocognitive disorders, cardiovascular disease and other comorbidities further threaten the health of an estimated 1.2 million HIV-infected people in the U.S. New therapeutic strategies capable of longer term virus suppression and reductions in the sources of persistent virus would relieve consequences of daily drug compliance and comorbidities for over 34 million HIV-infected people globally. Jericho Sciences’ investigational small molecule, FX101, is proposed to target the highly conserved zinc finger domains of lentiviral nucleocapsid (NC) proteins, a well-established therapeutic target for the treatment of HIV. FX101 has demonstrated preclinical safety and antiviral efficacy in multiple in vivo, ex vivo and in vitro models to support continuing translational testing. Zinc finger domains (ZFDs) of HIV nucleocapsid (NC) protein are highly conserved therapeutic targets shared across all lentiviruses, including feline, simian and human immunodeficiency viruses (FIV, SIV and HIV, respectively). Following eight monotherapeutic doses of FX101 over four weeks in chronically FIV-infected cats − one of the research models for HIV − blood plasma and cerebrospinal fluid viremia remained 85-95% below corresponding pretreatment levels up to 36 weeks following cessation of treatment, in the absence of observed or measured adverse events (p<0.0005; n=6; one-way ANOVA). These results are unprecedented in FIV-infected cats. Concurrently, integrated provirus in peripheral blood mononuclear cells continued to decrease by 95% from the normalized starting virus load (p<0.0001; n=6; one-way ANOVA). While we have yet to fully elucidate mechanistic implications of the nucleocapsid target profile, the most differentiating feature is the potential long term control of virus production in an apparent systemic reduction of virus replication setpoint. We propose here to conduct translational testing of FX101 in a simian immunodeficiency virus-infected nonhuman primate (SIV/NHP) model to establish the safety profile, therapeutic efficacy, and clinical biomarkers that may implicate this strategic candidate molecule’s potential utility toward a cotherapeutic functional eradication of HIV infection in humans. .