9
We are also evaluating ISIS-SMN
Rx
in aPhase 2open-label,multiple-dose, dose-escalationpilot study in infantswhohave
beendiagnosedwithSMA. In this study, we are evaluating twodose levels, 6 and12mg in infantswithSMA. We reported interim
results from this study inFebruary2014 showing that all four infants in the 6mg cohort hadbeenon study for over sixmonths and are
now approximatelynine and a half to16months in agewith an average age of approximately12 and a halfmonth. We reported that
all four infantswere alive andnone had requiredpermanent respiratory assistance. In addition, all four infants had tolerated
intrathecal administrationof ISIS-SMN
Rx
well. We plan to reportmore detailed results this study at theAmericanAcademy of
Neurologymeeting inApril 2014.
We plan to initiatePhase 3 studies inboth infants and childrenwithSMA in 2014. We are designing these studies to support
marketing registration for ISIS-SMN
Rx
in theUnitedStates andEurope.
We acknowledge support from the followingorganizations for this program:MuscularDystrophyAssociation, SMA
Foundation, andFamilies of SpinalMuscularAtrophy.We have licensed intellectual property fromColdSpringHarbor Laboratory
and theUniversityofMassachusettsMedical School.
ISIS-APOCIII
Rx
— ISIS-APOCIII
Rx
is an antisense drugwe designed to reduce apoC-III proteinproduction and lower
triglycerides. ApoC-III regulates triglyceridemetabolism in the blood and is an independent cardiovascular risk factor. This approach
is validated by the fact that peoplewho have certainmutations in the gene for apoC-III that result in lower levels of apoC-III have
lower levels of triglycerides and lower instances of cardiovascular disease. Also, peoplewith elevated levels of apoC-III have
increaseddyslipidemia associatedwithmultiplemetabolic abnormalities, such as insulin resistance and/ormetabolic syndrome. In
addition, peoplewith elevated triglycerides are at increased risk for type 2diabetes, andpeoplewith severely elevated triglycerides are
at high risk for acute pancreatitis andother serious conditions.
We are developing ISIS-APOCIII
Rx
for patientswithFCS andpatientswith severelyhigh triglycerides. FCS is a rare orphan
disease that affects an estimated3,000 to5,000peopleworldwide. FCSpatients oftenhave triglyceride levels higher than2,000
mg/dL and experience a number of healthproblems such as recurrent acute pancreatitis that often requires hospitalization, abdominal
pain, and enlargement of the liver and spleen. We believe that the significant unmetmedical need for an effective triglyceride-
loweringdrug for patientswithFCS and the robust, consistent effectswe observedwith ISIS-APOCIII
Rx
should enable us to rapidly
move this program forward toward themarket.
We are alsodeveloping ISIS-APOCIII
Rx
for the treatment of patientswith severelyhigh triglycerides. These are patients
with triglyceride levels greater than880mg/dLwho are also at a higher riskof pancreatitis andother serious conditions. For all
patientswho cannot reduce their triglycerides to acceptable levels, the primary therapy is diet, which requires strict adherence and is
oftenunsuccessful.
Inpreclinical studies, ISIS-APOCIII
Rx
diminished signs ofmetabolic syndrome and reduced atherosclerosis inmice. In a
Phase 1 study inhealthyvolunteers, ISIS-APOCIII
Rx
produced rapid, dose-dependentmedian reductions inbloodof up to78percent
in apoC-III protein levels andup to44percent in triglyceride levels.
We completed a broadPhase 2program evaluating ISIS-APOCIII
Rx
inpatientswithhigh, veryhigh, and severelyhigh
triglycerides, inpatientswith type 2diabetes and inpatientswithFCS. We also evaluated ISIS-APOCIII
Rx
both as a single agent and
in combinationwith fibrates. Patients in our Phase 2program enteredwithbaseline triglyceride levels ranging frommoderatelyhigh
to severelyhigh. In all patient groups studied, irrespectiveof their incoming triglyceride levels, treatmentwith ISIS-APOCIII
Rx
consistently reduced apoC-III, triglycerides and apoC-III-associatedVLDL complexes, and increasedHDL, with a positive effect on
non-HDL. Data from the 300mg/week dose from each of these studies are summarized in the table below.
