•
we may decide, or regulators may require us, to conduct additional preclinical testing or clinical
studies;
•
enrollment in our clinical studies may be slower than we anticipate;
•
the cost of our clinical studies may be greater than we anticipate; and
•
the supply or quality of our drugs or other materials necessary to conduct our clinical studies may be
insufficient, inadequate or delayed.
Any failure or delay in the clinical studies, including any further studies under the development program for
KYNAMRO and the Phase 3 studies for ISIS-APOCIII
Rx
, ISIS-SMN
Rx
and ISIS-TTR
Rx
, could reduce the
commercial potential or viability of our drugs.
If we cannot manufacture our drugs or contract with a third party tomanufacture our drugs at costs that
allow us to charge competitive prices to buyers, we cannot market our products profitably.
To successfully commercialize any of our drugs, we or our partner would need to establish large-scale
commercial manufacturing capabilities either on our own or through a third party manufacturer. In addition, as
our drug development pipeline increases and matures, we will have a greater need for clinical trial and
commercial manufacturing capacity. We have limited experience manufacturing pharmaceutical products of the
chemical class represented by our drugs, called oligonucleotides, on a commercial scale for the systemic
administration of a drug. There are a small number of suppliers for certain capital equipment and rawmaterials
that we use to manufacture our drugs, and some of these suppliers will need to increase their scale of production
to meet our projected needs for commercial manufacturing. Further, we must continue to improve our
manufacturing processes to allow us to reduce our drug costs. We may not be able to manufacture our drugs at a
cost or in quantities necessary to make commercially successful products.
Also, manufacturers, including us, must adhere to the FDA’s current GoodManufacturing Practices
regulations and similar regulations in foreign countries, which the applicable regulatory authorities enforce
through facilities inspection programs. We and our contract manufacturers may not comply or maintain
compliance with GoodManufacturing Practices, or similar foreign regulations. Non-compliance could
significantly delay or prevent receipt of marketing approval for our drugs, including additional approvals for
KYNAMRO, and initial approvals for ISIS-APOCIII
Rx
, ISIS-SMN
Rx
and ISIS-TTR
Rx
, or result in enforcement
action after approval that could limit the commercial success of our drugs, including KYNAMRO,
ISIS-APOCIII
Rx
, ISIS-SMN
Rx
and ISIS-TTR
Rx
.
We depend on third parties to conduct our clinical studies for our drugs and any failure of those parties to
fulfill their obligations could adversely affect our development and commercialization plans.
We depend on independent clinical investigators, contract research organizations and other third-party
service providers to conduct our clinical studies for our drugs and expect to continue to do so in the future. For
example, we use clinical research organizations, such as Icon Clinical Research Limited, INCResearch Toronto,
Inc. andMedpace for the clinical studies for our drugs, including KYNAMRO, ISIS-APOCIII
Rx
, ISIS-SMN
Rx
and ISIS-TTR
Rx
. We rely heavily on these parties for successful execution of our clinical studies, but do not
control many aspects of their activities. For example, the investigators are not our employees. However, we are
responsible for ensuring that these third parties conduct each of our clinical studies in accordance with the
general investigational plan and approved protocols for the study. Third parties may not complete activities on
schedule, or may not conduct our clinical studies in accordance with regulatory requirements or our stated
protocols. The failure of these third parties to carry out their obligations or a termination of our relationship with
these third parties could delay or prevent the development, approval and commercialization of our drugs,
including any expanded product label for KYNAMRO and initial approvals for ISIS-APOCIII
Rx
, ISIS-SMN
Rx
and ISIS-TTR
Rx
.
Risks Associated with our Businesses as aWhole
We have incurred losses, and our business will suffer if we fail to consistently achieve profitability in the
future.
Because drug discovery and development requires substantial lead-time and money prior to
commercialization, our expenses have generally exceeded our revenue since we were founded in January 1989.
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