Isis Pharmaceuticals, Inc. Form 10K - page 17

ISIS-GCCRRx —ISIS-GCCRRx is an antisense drug we designed to target the glucocorticoid receptor, or
GCCR. Glucocorticoid hormones affect a variety of processes throughout the body, and excessive levels of
glucocorticoid hormones can have a detrimental effect on many of the tissues and organs in the body. Cushing’s
Syndrome is an orphan disease caused by prolonged exposure to high levels of glucocorticoids. If untreated,
patients with Cushing’s Syndrome can develop hypertension, diabetes and impaired immune functions and have
an increased risk of early death. Although there are approved treatments for Cushing’s Syndrome, current
medicines are associated with significant side effects, such as hypertension and diabetes, and there remains a
high unmet medical need for new therapies for these patients. We have already demonstrated that subjects
tolerated ISIS-GCCRRx well in a Phase 1 study in healthy volunteers. For more information on ISIS-GCCR Rx
and type 2 diabetes, please refer to the ISIS-GCCRRx section under the subheading ‘‘Metabolic Disease
Franchise’’.
ISIS-PKKRx —ISIS-PKK Rx is an antisense drug we designed to inhibit the production of prekallikrein, or
PKK, a protein produced in the liver that plays an important role in the activation of inflammatory mediators
associated with acute attacks of hereditary angioedema, or HAE. HAE is a rare genetic disease that is
characterized by rapid and painful attacks of inflammation in the hands, feet, limbs, face, abdomen, larynx and
trachea. HAE affects approximately 20,000 patients in the United States and Europe and can be fatal if swelling
occurs in the larynx. In patients with frequent or severe attacks, doctors may use prophylactic treatment
approaches to prevent and reduce the severity of HAE attacks. However, current prophylactic treatment
approaches are very limited and have major tolerability issues due to challenging administration requirements
leaving patients with few therapeutic options. By inhibiting the production of PKK, ISIS-PKKRx could be an
effective prophylactic approach to preventing HAE attacks.
We have completed a Phase 1 study evaluating ISIS-PKKRx in healthy volunteers in which we observed up
to 95% reduction of PKK. In this study, ISIS-PKKRx was generally well tolerated.
We plan to initiate a Phase 2 clinical study evaluating ISIS-PKKRx in patients with hereditary angioedema in
2015.
Preclinical Development
The table below lists our preclinical drugs in our severe and rare disease franchise.
Drug Indication Partner
ISIS-HTTRx Huntington’s Disease Roche
ISIS-BIIB3Rx Neurodegenerative Disease Biogen Idec
ISIS-BIIB4Rx Neurodegenerative Disease Biogen Idec
RG-012 Alport Syndrome Regulus
ISIS-RHO-2.5Rx Autosomal Dominant Retinitis Pigmentosa GSK
ISIS-GHR-LRx Acromegaly Isis owned
Cardiovascular Franchise
Cardiovascular disease is the leading cause of death in the United States. Acommon cause of cardiovascular
disease is atherosclerosis, or premature plaque buildup, which occurs when cholesterol and inflammatory cells
accumulate in blood vessels. Researchers have shown a strong correlation between high cholesterol levels and
subsequent cardiovascular diseases. As such, lowering cholesterol is a key component in preventing and
managing cardiovascular disease.
Cardiovascular disease is an area of focus for us. We have created a cardiovascular disease franchise
comprised of drugs that target all the key components of cardiovascular disease, including various atherogenic
lipids, inflammation and thrombosis, an aberrant blood clot formation responsible for most heart attacks and
strokes. We have designed the majority of the drugs in our cardiovascular franchise to target cardiovascular risk
factors. These drugs make up our lipid franchise and include ISIS-APOCIIIRx, ISIS-APO(a)Rx and
ISIS-ANGPTL3Rx. ISIS-APOCIIIRx is the most advanced drug in this franchise and is designed to lower
apoC-III and triglycerides, which are both independent risk factors for cardiovascular disease. In addition, two
independent publications showed that people with rare mutations in theAPOCIII gene have lower triglyceride
levels and reduced risk of developing coronary heart disease. Results of these studies support the continued
advancement of ISIS-APOCIIIRx. Recent additions to our lipid franchise are our drugs that lower Lp(a) and
17