therapies to treat diabetes. One hurdle for traditional drug development is that most traditional drugs cannot
selectively target a disease-causing protein without also affecting closely related proteins, which often results in
unwanted side effects. We design our antisense drugs to target the gene responsible for producing the
disease-causing protein while avoiding unwanted effects on closely related proteins, thereby reducing the risk of
side effects.
We have reported positive Phase 2 data from ISIS-GCGR
Rx
and ISIS-PTP1B
Rx
, the most advanced drugs in
our metabolic franchise. These two drugs and our third drug, ISIS-GCCR
Rx
, are designed to act upon targets in
the liver or fat tissue through a distinct mechanism to improve insulin sensitivity, reduce glucose production, or
affect other metabolic aspects of this complex disease.
ISIS-GCGR
Rx
—ISIS-GCGR
Rx
is an antisense drug we designed to target the glucagon receptor, or GCGR,
to reduce the effects of glucagon. Glucagon is a hormone that opposes the action of insulin and stimulates the
liver to produce glucose, particularly in type 2 diabetes. In patients with advanced diabetes, uncontrolled
glucagon action leads to a significant increase in blood glucose levels. Therefore, attenuating glucagon action
could have a significant glucose lowering effect in patients with severe diabetes. In addition, reducing GCGR
produces more active glucagon-like peptide, or GLP-1, a hormone that preserves pancreatic function and
enhances insulin secretion.
We are developing ISIS-GCGR
Rx
to help provide better glucose control for patients with type 2 diabetes. In
preclinical studies using the most insulin-resistant models of type 2 diabetes, antisense reduction of GCGR
decreased excessive liver glucagon action, produced robust glucose control, reduced levels of triglycerides and
helped preserve the pancreas without producing hypoglycemia. Although researchers have developed and
evaluated small molecule inhibitors of GCGR and observed glucose-lowering effects, treatment with these small
molecule inhibitors also produced side effects, including increases in lipids and blood pressure, limiting their
potential use as drugs.
We have completed a Phase 1 study evaluating the safety of ISIS-GCGR
Rx
in healthy volunteers. In this
study ISIS-GCGR
Rx
was generally well tolerated with no clinically significant increases in lipids or blood
pressure and with no hypoglycemic events.
We have completed a Phase 2 placebo-controlled study evaluating ISIS-GCGR
Rx
in patients with type 2
diabetes. In June 2014, we reported these data at theAmerican Diabetes Association meeting. In this study, we
showed that patients treated with ISIS-GCGR
Rx
in addition to metformin achieved absolute mean reduction in
hemoglobinA1c, or HbA1c, of up to 2.25 percentage points from baseline after only 13 weeks of treatment.
Patients receiving placebo had a 0.25 percentage point reduction in HbA1c. In this study, more than half of the
patients in the per protocol cohort achieved an HbA1c level of less than or equal to 7.0 percent. Patients treated
with ISIS-GCGR
Rx
in this study also achieved a mean reduction of up to 74.9
µ
mol/L in fructosamine. In
addition, in these patients a mean increase in total GLP-1 of up to 19.97 pmol/Lwas observed.
In this study ISIS-GCGR
Rx
was generally well tolerated. The most common adverse event was infrequent
injection site reactions, which were predominantly mild and typically resolved rapidly. There were no flu-like
symptoms, no abnormalities in renal function and no cases of symptomatic hypoglycemia. ISIS-GCGR
Rx
was not
associated with clinically meaningful increases in LDL-C, triglycerides, blood pressure or body weight gain (side
effects associated with some small molecule inhibitors of glucagon receptor). As has been observed with small
molecule inhibitors of glucagon receptor and consistent with the pharmacology of glucagon receptor inhibition,
liver enzyme elevations that were neither associated with elevated bilirubin nor other indicators of liver damage
were observed. Liver enzyme elevations were much less frequent and lower in the 100 mg dose cohort compared
to the 200 mg dose cohort and declined after dosing discontinued. There were no clinically meaningful changes
in other laboratory values.
We plan to conduct additional studies to identify the optimal dose and schedule to achieve glucose control
with manageable glucagon receptor-related liver enzyme elevations. Given the unique mechanism of action and
good tolerability observed, we believe that doctors could use ISIS-GCGR
Rx
in diabetic patients with severe
hyperglycemia who are not controlled with current treatments and who could benefit from a drug that
significantly decreases glucose levels and preserves pancreatic function.
ISIS-GCCR
Rx
—ISIS-GCCR
Rx
is an antisense drug we designed to target the GCCR. Glucocorticoid
hormones effect a variety of processes throughout the body, including promoting liver glucose production and fat
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