PRO 542 Immunotherapy of Advanced HIV 1 Disease

描述(申请人提供)：尽管艾滋病毒-1治疗在过去十年中取得了重大进展，但大多数患者最终由于出现多药耐药病毒和出现无法耐受的治疗相关毒性而用尽了治疗选择。耐多药菌株的流行和传播加剧了这些挑战，因此，开发新的治疗战略仍然是一个高度优先的问题。 HIV-1的进入是通过一系列相互依赖的事件进行的，这些事件为治疗提供了有希望的靶点。这些事件包括gp20-CD4附着、gp120-共受体相互作用和gp41融合。这些步骤中每一步的抑制剂在对照临床试验中都显示出了希望。Pro 542(CD4-IgG2)是最先进的HIV-1附着抑制剂，在单剂量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感染抢救治疗的进入抑制剂，从而验证了病毒进入是可行的治疗目标。 单剂PRO 542在治疗晚期艾滋病毒-1疾病方面显示出特别的前景，在这种疾病中，最需要新的治疗选择；本项目试图将这些发现推广到多剂量环境中。拟议的2a期临床试验将检验在多达24名有治疗经验的晚期HIV-1感染患者中不断升级的多剂量PRO 542的耐受性、药代动力学和抗病毒效果。研究设计遵循了抗逆转录病毒治疗的基本原则，力求在3周的治疗期间保持统一的血药浓度，因此，这项研究旨在建立这一重要患者群体中多剂量PRO 542的明确概念证据。此外，还将测量治疗前后对PRO 542的病毒敏感性，并将其与临床结果相关联。病毒和药代动力学数据将被用来评估使用这种新药物进行有效治疗所需的阈值稳态药物浓度。第一阶段项目的成功将为第二阶段项目中扩大多剂量PRO 542的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这种药物与现有抗逆转录病毒药物联合使用时的治疗持久性，从而将作为关键的第三阶段研究的前奏。该项目的总体目标是加快PRO 542的开发，使其成为第一类潜在的HIV-1附着抑制物。

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.