Isis Pharmaceuticals, Inc. Form 10K - page 57

If we or our partners fail to obtain regulatory approval for our drugs, including additional approvals for
KYNAMRO or initial approvals for ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx, we or our partners
cannot sell them in the applicable markets.
We cannot guarantee that any of our drugs, including ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx, will
be safe and effective, or will be approved for commercialization. In addition, we cannot guarantee that
KYNAMROwill be approved in additional markets outside the United States or for additional indications. We
and our partners must conduct time-consuming, extensive and costly clinical studies to show the safety and
efficacy of each of our drugs, including KYNAMRO, ISIS-APOCIIIRx, ISIS-SMN Rx and ISIS-TTRRx, before
they can be approved for sale. We must conduct these studies in compliance with FDA regulations and with
comparable regulations in other countries.
We and our partners may not obtain necessary regulatory approvals on a timely basis, if at all, for any of
our drugs. It is possible that other regulatory agencies will not approve KYNAMRO or any of our other drugs
including, ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx for marketing. If the FDAor another regulatory
agency believes that we or our partners have not sufficiently demonstrated the safety or efficacy of any of our
drugs, including KYNAMRO, ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx, the agency will not approve the
specific drug or will require additional studies, which can be time consuming and expensive and which will
delay or harm commercialization of the drug. For example, inMarch 2013 the CHMP of the EuropeanMedicines
Agency maintained a negative opinion for Genzyme’s marketing authorization application for KYNAMRO as a
treatment for patients with HoFH.
Failure to receive marketing approval for our drugs, including KYNAMRO outside the United States or
initial approvals for ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx, or delays in these approvals could prevent
or delay commercial introduction of the drug, and, as a result, could negatively impact our ability to generate
revenue from product sales.
If the results of clinical testing indicate that any of our drugs are not suitable for commercial use we may
need to abandon one ormore of our drug development programs.
Drug discovery and development has inherent risks and the historical failure rate for drugs is high.
Antisense drugs are a relatively new approach to therapeutics. If we cannot demonstrate that our drugs are safe
and effective for human use, we may need to abandon one or more of our drug development programs. There are
ongoing clinical studies for KYNAMRO and sales to patients, adverse events fromwhich could negatively
impact our pending or planned marketing approval applications and commercialization of KYNAMRO.
In the past, we have invested in clinical studies of drugs that have not met the primary clinical end points in
their Phase 3 studies. Similar results could occur in any additional clinical studies for KYNAMRO and in clinical
studies for our other drugs, including ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx. If any of our drugs in
clinical studies, including KYNAMRO, ISIS-APOCIIIRx, ISIS-SMNRx and ISIS-TTRRx, do not show sufficient
efficacy in patients with the targeted indication, it could negatively impact our development and
commercialization goals for the drug and our stock price could decline.
Even if our drugs are successful in preclinical and human clinical studies, the drugs may not be successful
in late-stage clinical studies.
Successful results in preclinical or initial human clinical studies, including the Phase 3 results for
KYNAMRO and the Phase 2 results for some of our other drugs in development, may not predict the results of
subsequent clinical studies, including subsequent studies of KYNAMRO and the Phase 3 studies for
ISIS-APOCIIIRx, ISIS-SMN Rx and ISIS-TTRRx. There are a number of factors that could cause a clinical study
to fail or be delayed, including:
• the clinical study may produce negative or inconclusive results;
• regulators may require that we hold, suspend or terminate clinical research for noncompliance with
regulatory requirements;
• we, our partners, the FDAor foreign regulatory authorities could suspend or terminate a clinical study
due to adverse side effects of a drug on subjects in the trial;
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