In preclinical studies, ISIS-FXI
Rx
demonstrated potent antithrombotic activity with no increase in bleeding
compared with standard anti-clotting agents, including lowmolecular weight heparin, warfarin and Factor Xa
inhibitors, all of which increase bleeding.
We have completed a Phase 2 comparator-controlled study evaluating the incidence of venous
thromboembolic events, or VTE, in patients treated with ISIS-FXI
Rx
undergoing total knee replacement surgery,
or total knee arthroplasty, or TKA. In December 2014, we reported these data at theAmerican Society of
Hematology meeting and also published these data in the NewEngland Journal of Medicine. In this study, we
showed that ISIS-FXI
Rx
-treated patients experienced a dose-dependent decrease in venous thromboembolic
events. Patients treated with 300 mg of ISIS-FXI
Rx
experienced a seven-fold lower rate of VTE as compared
with those treated with enoxaparin (4.2% and 30.4%, respectively; p<0.001). Patients treated with 200 mg of
ISIS-FXI
Rx
had a rate of VTE comparable to that in patients treated with enoxaparin (26.9% and 30.4%,
respectively). The rate of VTE in patients given enoxaparin is within the range documented in previous studies in
this therapeutic setting. ISIS-FXI
Rx
treatment was associated with a dose-dependent and sustained reduction in
Factor XI activity that correlated with the lower rate of VTE. The rate of bleeding was lowwith ISIS-FXI
Rx
and
enoxaparin. We also reported that in this study, ISIS-FXI
Rx
was generally well tolerated. There were no observed
differences in safety outcomes compared with enoxaparin. In particular, there were no flu-like symptoms, and
injection site reactions were infrequent and mild. There have been no drug-related serious adverse events
reported to date.
We believe that there are a number of opportunities to develop ISIS-FXI
Rx
as an antithrombotic for patients
who require a safer and more effective agent. We plan to evaluate ISIS-FXI
Rx
in patient populations with an
unmet need in which relatively small studies can be conducted such as patients with atrial fibrillation, or AF, and
end-stage renal disease. We also believe that ISIS-FXI
Rx
can potentially be used in broader indications, including
in patients with mechanical heart valves and to prevent secondary cardiovascular events in patients with acute
coronary syndrome. In 2015 we plan to initiate a Phase 2 study in patients with renal failure.
ISIS-ANGPTL3
Rx
—ISIS-ANGPTL3
Rx
is an antisense drug we designed to reduceANGPTL3, an
independent risk factor for cardiovascular disease. ANGPTL3 is produced in the liver and regulates lipid, glucose
and energy metabolism. Humans with elevated levels of ANGPTL3 have hyperlipidemia that is associated with
an increased risk of premature heart attacks, increased arterial wall thickness as well as multiple metabolic
abnormalities, such as insulin resistance. In contrast, humans with lower levels of ANGPTL3 have lower LDL-C
and triglyceride levels and a lower risk of cardiovascular disease. In preclinical studies, antisense inhibition of
ANGPTL3 resulted in robust reductions of multiple lipid parameters, including total-cholesterol, LDL-C and
triglycerides.
ISIS-ANGPTL3
Rx
is part of our lipid franchise and, as such, we plan to transition development activities
associated with ISIS-ANGPTL3
Rx
toAkcea. We plan to complete a Phase 1 study evaluating ISIS-ANGPTL3
Rx
in healthy volunteers.
Preclinical Development
The table below lists our preclinical drugs in our cardiovascular disease franchise.
Drug
Indication
Partner
ISIS-AGT-L
Rx
Treatment-Resistant Hypertension
Isis owned
ISIS-ANGPTL3-L
Rx
Hyperlipidemia Disease
Akcea
ISIS-APO(a)-L
Rx
Very High Lp(a)
Akcea
ISIS-APOCIII-L
Rx
Severely High TGs
Akcea
ISIS-TMPRSS6-L
Rx
b-Thalassemia
Isis owned
Metabolic Franchise
Metabolic disorders are chronic diseases that affect millions of people. There is still a significant need for
new therapies for these patients. According to the Centers for Disease Control and Prevention, diabetes affects
more than 29 million people in the United States, or nine percent of the population, with type 2 diabetes
constituting 90 to 95 percent of those cases.
Metabolic disease is a very large area of medical need and is another area in which we focus our drug
discovery and development efforts. Our approach is to develop antisense drugs that doctors can add to existing
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