Integrated Safety Assessment of 2′-O-Methoxyethyl Chimeric Antisense Oligonucleotides in NonHuman Primates and Healthy Human Volunteers

被引：94

作者：

Crooke, Stanley T. ^{[1
]}

Baker, Brenda F. ^{[1
]}

Kwoh, T. Jesse ^{[1
]}

Cheng, Wei ^{[1
]}

Schulz, Dan J. ^{[1
]}

Xia, Shuting ^{[1
]}

Salgado, Nelson ^{[1
]}

Bui, Huynh-Hoa ^{[1
]}

Hart, Christopher E. ^{[1
]}

Burel, Sebastien A. ^{[1
]}

Younis, Husam S. ^{[1
,2
]}

Geary, Richard S. ^{[1
]}

Henry, Scott P. ^{[1
]}

Bhanot, Sanjay ^{[1
]}

机构：

[1] Ionis Pharmaceut Inc, 2855 Gazelle Court, Carlsbad, CA 92010 USA

[2] NGM Biopharmaceut, San Francisco, CA USA

来源：

MOLECULAR THERAPY | 2016年 / 24卷 / 10期

关键词：

B SYNTHESIS INHIBITION; APOLIPOPROTEIN C-III; PHASE-I; EFFICACY; THERAPY; RNA; PHARMACOKINETICS; SENSITIVITY; TECHNOLOGY; MIPOMERSEN;

D O I：

10.1038/mt.2016.136

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

The common chemical and biological properties of antisense oligonucleotides provide the opportunity to identify and characterize chemical class effects across species. The chemical class that has proven to be the most versatile and best characterized is the 2'-O-methoxyethyl chimeric antisense oligonucleotides. In this report we present an integrated safety assessment of data obtained from controlled dose-ranging studies in nonhuman primates (macaques) and healthy human volunteers for 12 unique 2'-O-methoxyethyl chimeric antisense oligonucleotides. Safety was assessed by the incidence of safety signals in standardized laboratory tests for kidney and liver function, hematology, and complement activation; as well as by the mean test results as a function of dose level over time. At high doses a number of toxicities were observed in nonhuman primates. However, no class safety effects were identified in healthy human volunteers from this integrated data analysis. Effects on complement in nonhuman primates were not observed in humans. Nonhuman primates predicted safe doses in humans, but over predicted risk of complement activation and effects on platelets. Although limited to a single chemical class, comparisons from this analysis are considered valid and accurate based on the carefully controlled setting for the specified study populations and within the total exposures studied.

引用

页码：1771 / 1782

页数：12

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