PRO 542 Immunotherapy of Advanced HIV 1 Disease

描述（由申请人提供）：尽管在过去十年中HIV-1治疗取得了重要进展，但由于多重耐药病毒的出现和无法耐受的治疗相关毒性的发展，大多数患者最终用尽了他们的治疗选择。多重耐药分离株的流行和传播日益增加，使挑战更加复杂，因此开发新的治疗策略仍然是一个高度优先事项。 HIV-1的进入通过一系列相互依赖的事件进行，这些事件为治疗提供了有希望的靶点。这些事件包括gp 120-CD 4附着、gp 120-辅助受体相互作用和gp 41融合。这些步骤中的每一个的抑制剂在对照临床试验中显示出希望。PRO 542（CD 4-IgG 2）是最先进的HIV-1附着抑制剂，在单次给药研究中显示出令人鼓舞的安全性和抗病毒特性。融合抑制剂T-20最近成为第一个获得FDA批准用于HIV-1感染挽救治疗的进入抑制剂，从而验证了病毒进入作为治疗的可行靶点。 单剂量PRO 542在治疗晚期HIV-1疾病方面表现出了特别的前景，其中对新治疗方案的需求最大;本项目旨在将这些发现扩展到多剂量环境。拟议的2a期临床试验将在多达24名有治疗经验的晚期HIV-1感染患者中检查PRO 542多次剂量递增的耐受性、药代动力学和抗病毒作用。研究设计遵循抗逆转录病毒治疗的基本原则，力求在整个3周治疗期间维持药物的统一血清谷浓度，因此该研究旨在为该重要患者人群中的多剂量PRO 542建立明确的概念验证。此外，将测量治疗前后对PRO 542的病毒易感性，然后将其与临床结局相关联。病毒和药代动力学数据将用于评估这种新药有效治疗所需的稳态药物浓度阈值。I期项目的成功将为II期项目中多剂量PRO 542的扩展临床试验提供强有力的支持和指导。扩大的临床研究将寻求确定与现有抗逆转录病毒药物联合使用时该药物治疗的持久性，因此将作为关键III期研究的前奏。该项目的总体目标是加快PRO 542的开发，使其成为第一种潜在的新型HIV-1附着抑制剂。

DESCRIPTION (provided by applicant): Despite important advances in HIV-1 therapy over the past decade, most patients eventually exhaust their therapeutic options due to the emergence of multidrug-resistant virus and to the development of intolerable treatment related toxicities. The challenges are compounded by the increasing prevalence and transmission of multidrug-resistant isolates, and thus the development of new treatment strategies remains a high priority. HIV-1 entry proceeds via a cascade of interdependent events that provide promising targets for therapy. These events gpl20-CD4 attachment, gp 120-coreceptor interactions, and gp41 fusion. Inhibitors of each of these steps have shown promise in controlled clinical trials. PRO 542 (CD4-IgG2) is the most advanced inhibitor of HIV-1 attachment, and has demonstrated encouraging safety and antiviral profiles in single-dose studies. The fusion inhibitor T-20 recently became the first entry inhibitor to receive FDA approval for salvage therapy of HIV-1 infection, thus validating viral entry as a viable target for therapy. Single-dose PRO 542 has demonstrated particular promise in treating advanced HIV-1 disease, where the need for new treatment options is greatest; and the present project seeks to extend these findings to the multidose setting. The proposed Phase 2a clinical trial will examine the tolerability, pharmacokinetics and antiviral effects of escalating, multiple doses of PRO 542 in up to 24 treatment-experienced patients with advanced HIV-1 infection. The study design adheres to fundamental principles of antiretroviral therapy in seeking to maintain uniform serum trough concentrations of drug throughout the 3-week treatment period, and thus the study is intended to establish clear proof-of-concept for multidose PRO 542 in this important patient population. In addition, viral susceptibility to PRO 542 preand post-treatment will be measured and then correlated with clinical outcome. The viral and pharmacokinetic data will be used to assess the threshold steady-state drug concentrations required for effective therapy with this new agent. Success in the Phase I project would provide strong support and guidance for expanded clinical trials of multidose PRO 542 in the Phase II project. The expanded clinical studies would seek to establish the durability of therapy with this agent when used in combination with existing antiretroviral medications and thus would serve as a prelude to pivotal Phase 3 studies. The overall goal of this project is to expedite development of PRO 542 as the first of a potential new class of inhibitors of HIV-1 attachment.