RACIVIR FOR TREATMENT OF HEPATITIS B AND HIV INFECTIONS

RACIVIR 用于治疗乙型肝炎和 HIV 感染

• 批准号: 6210647
• 负责人: MICHAEL J OTTO
• 金额: $ 14.2万
• 依托单位: PHARMASSET, INC.
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2001-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6210647
• 关键词: 2'3' dideoxynucleoside; HIV infections; antiAIDS agent; antiviral agents; dosage; drug adverse effect; drug screening /evaluation; hepatitis B; hepatitis B virus group; human immunodeficiency virus; laboratory rat; pharmacokinetics

Hepatitis B virus infection afflicts as many as 300 million people worldwide. Current therapy for chronically infected patients is suboptimal because of drug-related toxicity, low response rates and/or unsustained viral load reduction, and emergence of resistance. In addition, current drugs and compounds under development are quite costly making their availability to developing countries problematic. Effective long-term treatment with multiple low cost drugs will be required to address the needs of the majority of HBV- infected individuals. RacivirTM, (+/-)-beta-2,3' -dideoxy-3' -thia-5-fluorocytosine, [(+/-)KFC, RCV] is a 50:50 mixture of the two enantiomers of FTC. It has a similar virological profile when compared to (-)-beta-2',3' -dideoxy-3' -thia-5- fluorocytosine, [(-)-FTC, Coviracil, Emtricitabine], a drug with a proven safety and efficacy profile currently in Phase III clinical trials for HIV infections. Unlike (+)-BCH-189 (the plus-beta- enantiomer of 3TC), (+)- FTC is essentially non-toxic in various sophisticated in vitro toxicity assays. Like (-)-FTC and 3TC (Lamivudine) RCV is effective against HBV as well as HIV-1, HIV-2, and SIV (simian immunodeficiency virus) in vitro. Based on the cross-resistance profile, preliminary pharmacokinetic (PK) studies in SCID mice and in vitro selection studies with (+)-BCH-189, (+)-FTC, (-)- FTC, and RCV, we believe that RCV has a very desirable virological profile. We see RCV as a combined therapeutic modality, which is different from (-)-FTC and 3TC. This SBIR Phase 1 will focus on comparative PK and Toxicity studies in rats with Racivir and (+)-FTC. We wish to determine the maximum tolerated dose (MTD) of Racivir compared to (+)-FTC and establish a rationale, based on the safety profile, for proceeding to more advanced preclinical studies required for an IND filing for Racivir. The goal of the Phase 1 is to reach a decision point for the future development of Racivir. If the data indicate that Racivir has an acceptable toxicity profile in rats, then Phase 2 will focus on completing the preclinical safety and efficacy package required for an IND submission for Racivir, first as treatment for HBV infections and second as a treatment for HIV infections. PROPOSED COMMERCIAL APPLICATIONS: There is a need worldwide for effective, low cost, combination therapy for hepatitis B and HIV infections. Racivir has the potential to be superior to and less costly than the single enantiomers, FTC and 3TC. As such it should expand the market for effective treatments, especially in developing countries.

乙型肝炎病毒感染遭受了全球多达3亿人的困扰。 由于药物相关的毒性，低反应率和/或不固定的病毒负荷降低以及耐药性的出现，对慢性感染患者的当前治疗是次优的。 此外，目前正在开发的药物和化合物非常昂贵，使其对发展中国家有问题。需要多种低成本药物的有效长期治疗来满足大多数HBV感染者的需求。 Racivirtm，（+/-） - beta-2,3'-dideoxy-3'-thia-5-氟环胞嘧啶，[（+/-）kFC，RCV]是FTC的两个对映体的50:50混合物。与（ - ） - β-2'，3'-Dideoxy-3'-5- thia-5-荧光细胞肽相比，它具有相似的病毒学特征，[（ - ） - FTC，Coviracil，Emtricitabine]是一种在HIV III期临床试验中具有可培养的安全性和有效性的药物。与（+）-BCH-189（3TC的加苯甲酸抗体）不同，（+） - FTC在各种复杂的体外毒性测定中本质上是无毒的。类似于（ - ） - FTC和3TC（Lamivudine）RCV在体外对HBV以及HIV-1，HIV-2和SIV（Simian免疫缺陷病毒）有效。基于跨耐药性，在SCID小鼠和（+）-BCH-189，（+） - FTC，（ - ） - FTC和RCV的体外选择研究中进行初步药代动力学（PK）研究，我们相信RCV具有非常可取的病毒学特征。我们将RCV视为一种组合的治疗方式，与（ - ） - FTC和3TC不同。 SBIR 1阶段将集中于Racivir和（+）FTC大鼠的比较PK和毒性研究。我们希望与（+） - FTC相比，确定Racivir的最大耐受剂量（MTD），并根据安全性建立基本原理，以进行IND申请Racivir所需的更先进的临床前研究。第1阶段的目标是达到Racivir未来发展的决策点。如果数据表明Racivir在大鼠中具有可接受的毒性特征，则第2阶段将专注于完成IND提交Racivir所需的临床前安全性和功效包，首先是HBV感染的治疗方法，第二次作为治疗HIV感染的治疗方法。拟议的商业应用：全世界需要有效，低成本，乙型肝炎和艾滋病毒感染的组合疗法。 Racivir具有比单一对映异构体，FTC和3TC优于和成本更低的潜力。因此，它应该扩大有效治疗的市场，尤其是在发展中国家。