October 2014, we reported results from an analysis of spinal cord tissue samples from autopsies showing that
ISIS-SMN
Rx
is distributed throughout the central nervous system. The results of these analyses also showed
greater levels of full length SMN2 mRNAand full length SMN protein in tissues in ISIS-SMN
Rx
-treated SMA
infants compared to the levels of SMN2 mRNAand full length SMN protein in the tissues analyzed from
untreated SMA infants.
We are evaluating ISIS-SMN
Rx
in a Phase 2 open-label, multiple-dose, dose-escalation study in children
with SMA. We reported an update on this study in October 2014 at theWorldMuscle Society Congress with a
data cut off of September 2, 2014. In this study, we measured changes in muscle function scores using the
Hammersmith Functional Motor Scale-Expanded, or HFMSE, in children treated with multiple doses of
ISIS-SMN
Rx
. We reported that children in the 3 mg, 6 mg and 9 mg cohorts achieved mean increases in muscle
function scores from baseline of 1.7, 3.2 and 2.3, respectively, eight to 13 months after last dose. These data are
consistent with previously reported HFMSE scores for these children nine months after their last dose, which
were reported inApril 2014. We also reported that increases in muscle function scores were observed eight to
13 months after last dose in the six-minute walk test, or 6MWT, and the upper limb mobility, or ULM, test. In
the 6MWT, performed with 10 ambulatory children, a mean increase of 24.4 meters was observed 12 to 16
months after the patients’ baseline visits, compared to the previously reported increase of 22.7 meters at nine
months. In the ULM test, a mean increase of 3.1 points was observed 11 to 16 months after the patients’
baseline visits, compared to the previously reported increase of 2.3 points at nine months.
We are also evaluating ISIS-SMN
Rx
in a Phase 2 open-label, multiple-dose, dose-escalation study in 20
infants who have been diagnosed with SMA. We reported an update on this study in October 2014 with a data
cut off of September 2, 2014. We reported a median event-free age of 16.3 months in the infants in the 6 mg
cohort. For the infants in the 12 mg cohort, which began dosing five months after the initiation of dosing for the
6 mg cohort, we reported a median event-free age of 11.6 months. These data compared favorably to the natural
history of infants with SMAas published by the Pediatric Neuromuscular Clinical Research Network, or PNCR,
in the journal
Neurology
. As reported in October 2014, there had been four events (one permanent ventilation
and three deaths, all related to respiratory infections) in the 16 infants in the 12 mg cohort and two events (one
permanent ventilation and an accidental death) in the four infants in the 6 mg cohort. We also observed increases
in muscle function scores in infants from both dose cohorts.
The safety and tolerability profile of ISIS-SMN
Rx
to date supports continued development. The lumbar
puncture procedure in SMA infants and children has been well tolerated and shown to be feasible. Furthermore,
as of September 2014, we had administered a total of 250 intrathecal doses of ISIS-SMN
Rx
, and the procedure
was well tolerated. In all infants and children dosed, there have been no drug-related serious adverse events, or
SAEs. Most of the adverse events, or non-SAEs, have been mild or moderate in severity and not related to drug.
There were no changes in the safety profile with repeated doses of ISIS-SMN
Rx
.
We are evaluating ISIS-SMN
Rx
in two Phase 3 studies in infants and children with SMA. We designed these
studies to support marketing registration for ISIS-SMN
Rx
in the United States and Europe. The Phase 3 study,
ENDEAR, is a randomized, double-blind, sham-procedure controlled 13-month study in approximately 110
infants with SMA. In this study, we are evaluating the efficacy of ISIS-SMN
Rx
by measuring the time to
permanent ventilation or survival. The Phase 3 study, CHERISH, is a randomized, double-blind, sham-procedure
controlled 15-month study in approximately 117 children with SMA. In this study, we are evaluating the efficacy
of ISIS-SMN
Rx
by measuring changes in muscle function scores. We initiated both of these studies in 2014 and
plan to report data from both of these studies in the 2016/2017 timeframe.
We acknowledge support from the following organizations for this program: Muscular Dystrophy
Association, SMAFoundation, and Families of Spinal Muscular Atrophy. We have licensed intellectual property
fromCold Spring Harbor Laboratory and the University of Massachusetts Medical School.
ISIS-APOCIII
Rx
—ISIS-APOCIII
Rx
is an antisense drug we designed to reduce apoC-III protein production
and lower triglycerides. ApoC-III regulates triglyceride metabolism in the blood and is an independent
cardiovascular risk factor. The fact that people who have certain mutations 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 supports
our approach. Also, people with elevated levels of apoC-III have increased dyslipidemia associated with multiple
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