storage. Scientists associate excessive GCCR activity in the liver and fat with obesity, insulin resistance and
glucose intolerance. Although scientists have long recognized inhibiting GCCR as an attractive strategy for
improving glycemic and lipid control in patients with type 2 diabetes, the side effects associated with systemic
GCCR inhibition have challenged traditional drug developers. Our antisense inhibitor of GCCR takes advantage
of the unique tissue distribution of oligonucleotides that allows our drug to inhibit glucocortocoid action
primarily in liver and fat tissue. Notably, antisense drugs delivered systemically do not reduce GCCR expression
in the central nervous system or adrenal glands, which could lead to systemic side effects. Reducing GCCR
specifically in the liver and fat tissues is an attractive therapeutic approach because it lowers glucose and lipids,
without causing potential side effects associated with systemic GCCR inhibition.
In preclinical studies, we showed that we can reduce GCCR specifically in the liver and fat tissues. In
addition, we have shown that antisense inhibition of GCCR produced robust lowering of blood glucose, lipid
levels and decreased body fat in obese animals. We have completed a Phase 1 study evaluating the safety of
ISIS-GCCR
Rx
in healthy volunteers. In this study, ISIS-GCCR
Rx
was generally well tolerated and we observed
reductions of GCCR specifically in the liver and fat tissues, consistent with our preclinical observations.
We believe that doctors could use ISIS-GCCR
Rx
in diabetic patients with moderate to severe hyperglycemia
who are also obese or have high levels of cholesterol and triglycerides. We also believe that there are other
attractive therapeutic opportunities for doctors to use ISIS-GCCR
Rx
in patients with diseases in which there is
glucocorticoid excess, such as Cushing’s Syndrome, and other diseases where a selective GCCR inhibitor could
be beneficial. For more information on ISIS-GCCR
Rx
and Cushing’s Syndrome, please refer to the ISIS-GCCR
Rx
section under the subheading ‘‘Severe and Rare Disease Franchise’’.
We plan to report data from a Phase 2 study of ISIS-GCCR
Rx
in patients with type 2 diabetes in
combination with metformin in 2015.
ISIS-PTP1B
Rx
—ISIS-PTP1B
Rx
is an antisense drug we designed to target protein tyrosine
phosphatase-1B, or PTP-1B, to treat type 2 diabetes. PTP-1B is a phosphatase that negatively regulates insulin
receptor signaling and is responsible for turning off the activated insulin receptor. Reducing PTP-1B enhances
insulin activity. Scientists have long recognized PTP-1B as an attractive target to treat diabetes, but due to
structural similarities among closely related proteins, pharmaceutical companies have had difficulty identifying
small molecule drugs with sufficient specificity to be safe. We designed ISIS-PTP1B
Rx
to increase the body’s
sensitivity to the natural hormone, insulin, resulting in better glucose control for patients with type 2 diabetes.
Because of its unique mechanism, ISIS-PTP1B
Rx
may help treat patients with type 2 diabetes without causing
weight gain or hypoglycemia, also known as low blood sugar. The reductions in LDL-C produced by inhibiting
PTP-1B should also provide an added benefit to patients.
We have completed a Phase 1 study evaluating the safety of ISIS-PTP1B
Rx
in healthy volunteers. In this
study, subjects tolerated ISIS-PTP1B
Rx
well. We also observed encouraging data in measures of insulin
sensitivity and in a biomarker associated with weight loss. These Phase 1 data are consistent with our findings
from our Phase 2 ISIS 113715 studies and support our preclinical observations of increased potency with
ISIS-PTP1B
Rx
compared to ISIS 113715.
We reported top-line data from a Phase 2 study of ISIS-PTP1B
Rx
in patients with type 2 diabetes with or
without sulfonylurea therapy. In this study, patients treated with ISIS-PTP1B
Rx
achieved statistically significant
reductions in body weight and HbA1c. In patients treated with ISIS-PTP1B
Rx
, a mean reduction in HbA1c of
0.7 percentage points from baseline was achieved at 36 weeks, compared to a mean reduction of 0.2 percentage
points for placebo-treated patients (p=0.03). Patients treated with ISIS-PTP1B
Rx
also experienced a statistically
significant mean reduction in body weight from baseline at 36 weeks (p=0.01). Patients received 200 mg of
ISIS-PTP1B
Rx
or placebo for 26 weeks added to their stable doses of their background therapies. In this study,
the average incoming HbA1c level was 8.6 percent and the average BMI was 34 kg/m2. Patients in this study
were not required to conform to any type of restrictive or weight-loss diet beyond the standard dietary
restrictions they adhered to upon entry into the study. In this study ISIS-PTP1B
Rx
was generally well tolerated.
The most common adverse event was infrequent injection site reactions, which were predominantly mild and
resolved rapidly. We plan to report the full data from this study at a scientific meeting in 2015.
We believe that physicians may use ISIS-PTP1B
Rx
in combination with most of the other commonly used
diabetes drugs, including insulin, GLP-1 agonists, and more traditional drugs like metformin, to treat patients
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