The complementary nucleotide chain that binds specifically to the sense strand is called the ‘‘antisense’’ strand.
We use the information contained in RNA to design chemical structures, called antisense oligonucleotides or
antisense drugs, which resemble DNAand RNAand are the complement of RNA. These potent antisense drugs
inhibit the production of disease-causing proteins or reduce harmful RNAs. Specifically, almost all of our
antisense drugs in development cause a cellular enzyme called ribonuclease H1, or RNase H1, to degrade the
target RNA. The drug itself remains intact during this process, so it can remain active against additional target
mRNAmolecules and repeatedly trigger their degradation. Our antisense drugs can selectively bind to an mRNA
that codes for a specific protein and will not bind to closely related RNAs, providing a level of specificity that is
better than traditional drugs. As a result, we can design antisense drugs that selectively inhibit the
disease-causing member of the group without interfering with those members of the group necessary for normal
bodily functions. This unique specificity means that antisense drugs may be less toxic than traditional drugs
because we can design them to minimize the impact on unintended targets.
Further, the design of antisense compounds is less complex, more rapid and more efficient than traditional
drug discovery approaches directed at protein targets. Traditional drug design requires companies to identify a
small molecule that will interact with protein structures to affect the disease-causing process. Since predicting
which small molecules will do this has proven to be difficult, traditional drug discovery involves testing
hundreds of thousands of small molecules for their ability to interfere with protein function. As a result,
traditional drug discovery is a labor intensive, low probability endeavor. In contrast, we design our antisense
compounds to bind to RNA through well understood processes. We can design prototype antisense drugs as soon
as we identify the sequence for the target RNA.
Using proprietary antisense oligonucleotides to identify what a gene does, called gene functionalization, and
then determining whether a specific gene is a good target for drug discovery, called target validation, are the first
steps in our drug discovery process. We use our proprietary antisense technology to generate information about
the function of genes and to determine the value of genes as drug discovery targets. This efficiency represents a
unique advantage of our antisense drug discovery process. Antisense core technology is the function within Isis
that is responsible for advancing antisense technology. Through the efforts of our scientists in the antisense core
technology group, we have produced second generation antisense drugs that have increased potency and stability.
In recent years, our scientists have improved the screening assays for our drugs, which led to the discovery of
second generation antisense drugs that have generally demonstrated enhanced tolerability profiles in numerous
clinical studies. For example, our drugs ISIS-TTR
Rx
and ISIS-FXI
Rx
are drugs we discovered through our
improved screening assays. In Phase 1 studies evaluating these drugs in healthy volunteers, subjects reported
approximately 65 percent fewer injection site reactions and no flu-like symptoms compared to subjects treated
with KYNAMRO, an earlier second generation drug.
We combine our core technology programs in medicinal chemistry, RNAbiochemistry, and molecular and
cellular biology with molecular target-focused drug discovery efforts to design drugs. The goal of our
target-based research programs is to identify antisense drugs to treat diseases for which there is a large unmet
medical need. These include diseases that are severe and rare and diseases for which there are limited or no
current treatments or in diseases for which we believe our drugs have a competitive advantage over existing
therapies. In addition, our research programs focus on the planned advancement of our technology for future
antisense drugs. We are designing drugs using our next generation chemistry, generation 2.5, an advancement that
we believe increases the potency of our drugs by up to 10-fold and could have the potential to make oral
administration commercially feasible. We have published data demonstrating that our generation 2.5 drugs
generally have enhanced potency over our generation 2.0 drugs and are broadly distributed throughout the body
to multiple tissues including liver, kidney, lung, muscle, adipose, adrenal gland and peripheral nerves. Our
generation 2.5 drugs constitute some of our recently added new drugs. We notate in our pipeline which drugs
incorporate our generation 2.5 chemistry by appending a 2.5 at the end of the drug name. Currently
ISIS-STAT3-2.5
Rx
, ISIS-DMPK-2.5
Rx
, ISIS-AR-2.5
Rx
, and ISIS-RHO-2.5
Rx
incorporate our generation 2.5
chemistry.
In addition to improving the chemical foundation of our drugs, we have also created a technology suite,
LICA, designed to enhance the delivery of our drugs to particular tissues. We believe that our LICA technology
could further enhance the potency of our drugs. For example, our LICA technology directed toward liver targets
produced a ten-fold increase in potency in preclinical studies in both our second-generation and our generation
2.5 drugs. We currently have eight second generation-LICAdrugs in our pipeline, ISIS-AGT-L
Rx
,
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