8
We completed aPhase 1 study evaluating the safety and activityof ISIS-TTR
Rx
inhealthyvolunteers. In this study, ISIS-
TTR
Rx
produced rapid, dose-dependent reductions inplasmaTTRproteinwith an average of 75percent reduction inTTRprotein,
with some subjects achieving approximately90percent reduction. In addition, therewere several subjects that reachedTTRprotein
levels thatwere below the limit of assaydetection. Subjects treatedwith ISIS-TTR
Rx
generally tolerated the drugwell. In
February 2013, we initiated aPhase 3 study to evaluate the efficacy of ISIS-TTR
Rx
in patientswithFAP. In this study, we plan to
enroll approximately 200patients and evaluate the efficacy of ISIS-TTR
Rx
bymeasuringneurological dysfunction andqualityof life
in patientswithFAP.
ISIS-SMN
Rx
— ISIS-SMN
Rx
is an antisense drugwe designed to treat SMA, a severemotor-neurondisease that is the leading
genetic cause of infantmortality. SMA affects approximately30,000 to35,000patients in theUnitedStates, Europe and Japan. One in
50people, approximately sixmillion people in theUnitedStates, carry the genemutation that causes SMA. Carriers experience no
symptoms anddonot develop the disease.When both parents are carriers, however, there is a one in four chance that their childwill
haveSMA. SMA is causedby a loss of, or defect in, the survivalmotor neuron1, or SMN1, gene leading to a decrease in the protein,
survivalmotor neuron, or SMN. SMN is critical to the health and survival of nerve cells in the spinal cord that are responsible for
neuro-muscular growth and function. The severityof SMA correlateswith the amount of SMNprotein. InfantswithType I SMA, the
most severe life-threatening form, produce very little SMN protein andhave a significantly shortened life expectancy. Childrenwith
Type II andType III SMAhave greater amounts of SMNprotein andhave less severe, but still life-altering, forms of SMA. The FDA
grantedOrphanDrugDesignationwithFast TrackStatus to ISIS-SMN for the treatment of patientswithSMA.
In January2012, we andBiogen Idec entered into a preferredpartner alliance that providesBiogen Idec anoption todevelop
and commercialize ISIS-SMN
Rx
. Under the agreement, we received an upfront fee and are responsible for developing ISIS-SMN
Rx
.
Biogen Idec has the option to license ISIS-SMN
Rx
until completion of the first successful Phase 2/3 study or the completion of two
Phase 2/3 studies.We are eligible to receivemilestone payments fromBiogen Idec as ISIS-SMN
Rx
advances throughdevelopment.
We designed ISIS-SMN
Rx
topotentially treat all types of childhoodSMAby altering the splicingof a closely relatedgene,
SMN2, which leads to the increasedproductionof fully functional SMNprotein.We developed a biomarker assay tomeasure levels
of SMNprotein in the cerebral spinal fluidof children and infantswithSMA. InFebruary2014, we reported the first set of data using
this biomarker assay. Using this assay, we observeddose-dependent increases inSMNprotein levels in childrenwithSMA treated
with ISIS-SMN
Rx
fromboth the single- andmultiple-dose studies. In the single-dose study, SMNprotein levelsmore thandoubled in
the twohighest dose cohorts, 6 and9mg, with average increases of approximately120percent and160percent compared tobaseline,
respectively, approximatelynine to14months after dosing. Similarly, in themultiple-dose study, we observed substantial increases
inSMNprotein levels in the 9mg cohort of 115percent compared tobaseline approximately threemonths, or day86, after the first
dose.
InMarch2013, we reported encouragingdata from a single-dose, open-label Phase 1 clinical study evaluating ISIS-SMN
Rx
in
childrenwithSMA. In this study, we reported that ISIS-SMN
Rx
waswell toleratedwhen administered intrathecally as a single dose
directly into the spinal fluid. In addition, the children tolerated the intrathecal injectionprocedurewell.We also showed that
concentrations of ISIS-SMN
Rx
measured in cerebral spinal fluidwere consistentwith levels predicted frompreclinical studies,
indicating that the drughalf-life innervous system tissues is very long and that dosingonce every six toninemonths is feasible.
Although the studywas not designed toprovide evidence of functional activity, we observed increases in theHammersmith
FunctionalMotor Scale-Expanded, orHFMSE, ameasure ofmuscle function, in a number of these children. Themean increase in the
HFMSE scores observed in the highest dose cohort (9mg) at 3monthswas 3.1points or a 17.6% increase frombaseline, with sixof
ten patients experiencing an increase of greater than four points. Observed increases inHFMSE scores equal toor greater than a 4
point compared tobaselinewere distributedby agewithhalf in childrenunder the age of five andhalf in children five andolder.
InSeptember 2013, we reported a follow-up analysis of the single-dose, open-label Phase 1 studyof ISIS-SMN
Rx
in children
withSMA. In this study, we observed thatmost childrenwithSMAwho received a single dose of one of the twohighest doses of
ISIS-SMN
Rx
, 6mg or 9mg, continued to show increases inmuscle function scores up to14months after a single injectionof the drug.
We are evaluating ISIS-SMN
Rx
in aPhase 2open-label,multiple-dose, dose-escalation study in childrenwithSMA. In this
study, we are evaluating four dose levels, 3, 6, 9, and12mg in childrenwithSMA ages two to15. We reported interim results from
the 3, 6 and9mg cohorts from this study inFebruary2014 showing that treatmentwith ISIS-SMN
Rx
waswell tolerated. In addition,
we observed dose- and time-dependent increases inHFMSE scores in children treatedwithmultiple doses of ISIS-SMN
Rx
. Children
in the 3mg, 6mg, and9mg cohorts achievedmean increases inHFMSE scores of 1.5, 2.3 and3.7points, respectively, ninemonths
following the first dose of ISIS-SMN
Rx
. Children in the 9mg cohort achievedmean increases inHFMSE scores of 2.7 and3.7points
three andninemonths after the first dose of ISIS-SMN
Rx
, respectively.
Rx
