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Advancing antisense core chemistry has been a central focus of the
Company’s research efforts. Medicinal chemistry involves the
modification of a compound by altering its structure, composition
or charge to enhance drug qualities. Such modifications can improve
a drug’s stability in the body, its ability to move into certain
tissues and cells, its specificity and binding strength for its
intended target, its side effect profile and its ability to be safely
metabolized and eliminated from the body. The Company's medicinal
chemistry group has contributed to Isis’ leadership and patent
position in antisense technology.
Isis has built a robust pipeline of antisense drugs based on two
distinct classes of chemistry.
Isis'
first-generation chemistry (phosphorothioate oligodeoxynucleotides)
First-generation antisense drugs are used to treat both local and
systemic diseases. Isis has a first-generation drug in clinical
trials for the treatment of ulcerative colitis. These antisense
drugs have a sulfur chemistry modification that makes the drug more
resistant to degradation, increasing stability in the blood stream
and in tissues. This specific chemical modification prevents the
rapid elimination of the drug from the body. First-generation agents
can be delivered via intravitreal injection, parenterally, by
topical cream, enema, and inhaled aerosol.
Isis'
second-generation chemistry (called 2'-O-methoxyethyl or
2'MOE)
Isis scientists identified the Company’s proprietary 2’-methoxyethyl
(2’MOE) chemistry after creating and testing hundreds of chemical
modifications. Isis’ pipeline currently consists of second-generation
compounds in various stages of development to treat cardiovascular, metabolic and inflammatory diseases. Isis’ partners are focused in disease areas such as ocular, viral and neurodegenerative diseases, and cancer.
Isis’ second-generation chemistry adds 2’MOE modifications
to the sulfur modification of first-generation chemistry. In turn,
second-generation drugs have increased target binding affinity and
resistance to degradation.
The improved affinity of second-generation drugs is primarily attributable
to their design and composition. Second-generation drugs are composed
of both RNA-like and DNA-like nucleotides, while first-generation
drugs are entirely DNA-like. Because RNA hybridizes more tightly
to RNA than to DNA, the second-generation drugs have a greater affinity
for their RNA targets and, therefore, greater potency. With increased
potency, Isis’ second-generation drugs are active at lower
doses, which can decrease the overall cost of therapy.
Additionally, second-generation chemistry significantly slows degradation
of the drugs by protecting them from nucleases, the molecules responsible
for disassembling strands of nucleotides. Slower clearance of the
drug from the body allows for less frequent dosing, and offers the
potential for oral delivery. Each of these second-generation enhancements
will improve patient convenience.
Formulations
Chemistry advancements have been paralleled by the development
of new formulations that expand the therapeutic and commercial opportunities
of Isis’ pipeline. Antisense drugs are being studied in aerosol, enema, intrathecal, intravenous, subcutaneous, intravitreal, oral and topical formulations.
