14
We have completed a Phase 1 study evaluating the safety of ISIS-GCGR
Rx
inhealthyvolunteers. In this study, subjects
tolerated ISIS-GCGR
Rx
well withno clinically significant increases in lipids or bloodpressure andwithnohypoglycemic events. In
addition, we observed an increase in totalGLP-1, whichwas consistentwith our preclinical observations.
Given the uniquemechanismof action andgood tolerability observed in thePhase 1 study, we believe that doctors could use
ISIS-GCGR
Rx
in diabetic patientswith severe hyperglycemiawho are not controlledwith current treatments andwho couldbenefit
from a drug that significantlydecreases glucose levels andpreserves pancreatic function.
We are currently evaluating ISIS-GCGR
Rx
in aPhase 2 study inpatientswith type 2diabeteswho, despite takingmetformin,
have uncontrolled glucose levels.
ISIS-GCCR
Rx
— ISIS-GCCR
Rx
is an antisense drug that targets glucocorticoid receptor, orGCCR. Glucocorticoid hormones
effect a varietyof processes throughout the body, includingpromoting liver glucose production and fat storage. Scientists associate
excessiveGCCR activity in the liver and fatwithobesity, insulin resistance andglucose intolerance. Although scientists have long
recognized inhibitingGCCR as an attractive strategy for improvingglycemic and lipid control inpatientswith type 2diabetes, the
side effects associatedwith systemicGCCR inhibitionhave challenged traditional drugdevelopers. Antisense inhibitors ofGCCR
take advantage of the unique tissue distributionof oligonucleotides that allows the antisense drugs to inhibit glucocortocoid action
primarily in liver and fat tissue. Notably, antisense drugs delivered systemically donot reduceGCCR expression in the central
nervous systemor adrenal glands, which could lead to systemic side effects. ReducingGCCR specifically in the liver and fat tissues is
an attractive therapeutic approachbecause it lowers glucose and lipids, without causingpotential side effects associatedwith systemic
GCCR inhibition.
In preclinical studies, we showed thatwe can reduceGCCR specifically in the liver and fat tissues. In addition, we have
shown that antisense inhibitionofGCCRproduced robust loweringof bloodglucose, lipid levels anddecreasedbody fat in obese
animals.We have completed aPhase 1 study evaluating the safetyof ISIS-GCCR
Rx
inhealthyvolunteers. In this study, subjects
tolerated ISIS-GCCR
Rx
well, andwe observed reductions ofGCCR specifically in the liver and fat tissues, consistentwithour
preclinical observations.
We believe that doctors coulduse ISIS-GCCR
Rx
in diabetic patientswithmoderate to severe hyperglycemiawho are also
obese or have high levels of cholesterol and triglycerides.We alsobelieve that there are other attractive therapeutic opportunities for
doctors touse ISIS-GCCR
Rx
inpatientswithdiseases inwhich there is glucocorticoid excess, such asCushing’s Syndrome, andother
diseaseswhere a selectiveGCCR inhibitor couldbe beneficial.We plan todevelop ISIS-GCCR
Rx
to treat patientswithCushing’s
Syndrome. Formore informationon ISIS-GCCR
Rx
andCushing’s Syndrome, please refer to the ISIS-GCCR
Rx
sectionunder the
subheading “Severe andRareDiseaseFranchise”.
We are currently evaluating ISIS-GCCR
Rx
in aPhase 2 study inpatientswith type 2diabetes in combinationwithmetformin
andplan to initiate aPhase 2 study evaluating ISIS-GCCR
Rx
inpatientswithCushing’s Syndrome in 2014.
ISIS-PTP1B
Rx
— ISIS-PTP1B
Rx
is an antisense drug that targets 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 turningoff the activated
insulin receptor. ReducingPTP-1B enhances insulin activity. Scientists have long recognizedPTP-1B as an attractive target to treat
diabetes, but due to structural similarities among closely related proteins, pharmaceutical companies have had difficulty identifying
smallmolecule drugswith sufficient specificity to be safe.We designed ISIS-PTP1B
Rx
to increase the body’s sensitivity to the natural
hormone, insulin, resulting inbetter glucose control for patientswith type 2diabetes. Because of its uniquemechanism, ISIS-PTP1B
Rx
mayhelp treat patientswith type 2diabeteswithout causingweight gainor hypoglycemia, alsoknown as lowblood sugar. The
reductions inLDL-Cproducedby inhibitingPTP-1B should alsoprovide an addedbenefit to patients.
Phase 2 studies of ISIS113715, our previous PTP-1B inhibitor, showed that inhibitingPTP-1B couldhelppatientswith type
2diabetes. In those studies, inhibitingPTP-1B improvedglucose control and reducedLDL-C inbothnewlydiagnoseddiabetic
patients and inpatientswhowere taking sulfonylureas. Drug-treatedpatients in these studies alsodidnot experienceweight gain,
indicating another substantial advantage in treatingdiabetic patients, who are frequentlyobese and at high cardiovascular risk.
We have completed a Phase 1 study evaluating the safety of ISIS-PTP1B
Rx
inhealthyvolunteers. In this study, subjects
tolerated ISIS-PTP1B
Rx
well.We alsoobserved encouragingdata inmeasures of insulin sensitivity and in a biomarker associatedwith
weight loss. These Phase 1data are consistentwithour findings fromour Phase 2 ISIS113715 studies and support our preclinical
observations of increasedpotencywith ISIS-PTP1B
Rx
compared to ISIS113715.
