A Randomized, Double-Blind, Placebo-Controlled, Single-Dose, Dose-Escalation Study to Assess the Safety, Tolerability and Pharmacokinetics of AVI-6003 in Healthy Adult Volunteers

The purpose of this study is to characterize the safety and pharmacology of single administrations of AVI-6003, a post-exposure prophylaxis candidate treatment for Marburg virus.

开始日期2011-05-01

申办/合作机构

Sarepta Therapeutics, Inc.

100 项与 AVI-6003 相关的临床结果

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100 项与 AVI-6003 相关的转化医学

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100 项与 AVI-6003 相关的专利（医药）

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项与 AVI-6003 相关的文献（医药）

2014-11-01·Antimicrobial Agents and Chemotherapy2区 · 医学

Safety and Pharmacokinetic Profiles of Phosphorodiamidate Morpholino Oligomers with Activity against Ebola Virus and Marburg Virus: Results of Two Single-Ascending-Dose Studies

2区 · 医学

Article

作者: Saoud, Jay B. ; Wong, Michael ; Charleston, Jay S. ; Heald, Alison E. ; Kaye, Edward ; Sazani, Peter ; Iversen, Patrick L. ; Axtelle, Tim ; Vutikullird, Apinya ; Smith, William B.

ABSTRACT Two identical single-ascending-dose studies evaluated the safety and pharmacokinetics (PK) of AVI-6002 and AVI-6003, two experimental combinations of phosphorodiamidate morpholino oligomers with positive charges (PMO plus ) that target viral mRNA encoding Ebola virus and Marburg virus proteins, respectively. Both AVI-6002 and AVI-6003 were found to suppress disease in virus-infected nonhuman primates in previous studies. AVI-6002 (a combination of AVI-7537 and AVI-7539) or AVI-6003 (a combination of AVI-7287 and AVI-7288) were administered as sequential intravenous (i.v.) infusions of a 1:1 fixed dose ratio of the two subcomponents. In each study, 30 healthy male and female subjects between 18 and 50 years of age were enrolled in six-dose escalation cohorts of five subjects each and received a single i.v. infusion of active study drug (0.005, 0.05, 0.5, 1.5, 3, and 4.5 mg/kg per component) or placebo in a 4:1 ratio. Both AVI-6002 and AVI-6003 were safe and well tolerated at the doses studied. A maximum tolerated dose was not observed in either study. The four chemically similar PMO plus components exhibited generally similar PK profiles. The mean peak plasma concentration and area under the concentration-time curve values of the four components exhibited dose-proportional PK. The estimated plasma half-life of all four components was 2 to 5 h. The safety of the two combinations and the PK of the four components were similar, regardless of the target RNA sequence.

Viruses3区 · 医学

Discovery and Early Development of AVI-7537 and AVI-7288 for the Treatment of Ebola Virus and Marburg Virus Infections

3区 · 医学

ArticleOA

作者: Panchal, Rekha G. ; Iversen, Patrick L. ; Bavari, Sina ; Warren, Travis K. ; Wells, Jay B. ; Welch, Lisa S. ; Mourich, Dan V. ; Garza, Nicole L.

There are no currently approved treatments for filovirus infections. In this study we report the discovery process which led to the development of antisense Phosphorodiamidate Morpholino Oligomers (PMOs) AVI-6002 (composed of AVI-7357 and AVI-7539) and AVI-6003 (composed of AVI-7287 and AVI-7288) targeting Ebola virus and Marburg virus respectively. The discovery process involved identification of optimal transcript binding sites for PMO based RNA-therapeutics followed by screening for effective viral gene target in mouse and guinea pig models utilizing adapted viral isolates. An evolution of chemical modifications were tested, beginning with simple Phosphorodiamidate Morpholino Oligomers (PMO) transitioning to cell penetrating peptide conjugated PMOs (PPMO) and ending with PMOplus containing a limited number of positively charged linkages in the PMO structure. The initial lead compounds were combinations of two agents targeting separate genes. In the final analysis, a single agent for treatment of each virus was selected, AVI-7537 targeting the VP24 gene of Ebola virus and AVI-7288 targeting NP of Marburg virus, and are now progressing into late stage clinical development as the optimal therapeutic candidates.

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