Designation for the treatment of pouchitis in the United States and Europe, respectively. We are eligible to
receive royalties on product sales, including product sales under the named patient supply program fromAtlantic
Pharmaceuticals. Atlantic Pharmaceuticals is currently pursuing opportunities to fund further development of
alicaforsen.
ISIS-TTR
Rx
—ISIS-TTR
Rx
is an antisense drug we designed to treat TTR amyloidosis, a severe and rare
genetic disease in which the patient inherits a mutant gene that produces a misfolded form of TTR, which
progressively accumulates in tissues. In patients with TTR amyloidosis, both the mutant and normal forms of
TTR can build up as fibrils in tissues, such as the heart, peripheral nerves, and the GI tract. The presence of TTR
fibrils interferes with the normal functions of these tissues, and as the TTR protein fibrils enlarge, more tissue
damage occurs and the disease worsens.
We are evaluating ISIS-TTR
Rx
to treat two types of TTR amyloidosis, familial amyloid cardiomyopathy, or
FAC, which affects more than 40,000 patients worldwide, and familial amyloid polyneuropathy, or FAP, which
affects more than 10,000 patients worldwide. Patients with FAC have TTR build up in the heart muscle and
succumb to heart failure approximately five to six years after symptom onset. Patients with FAP have TTR build
up in peripheral nerve tissue leading to the loss of nerve function and wasting.
ISIS-TTR
Rx
is the first drug to enter development under our preferred partner alliance with GSK. We
designed ISIS-TTR
Rx
to inhibit the production of all forms of TTR, and to offer an alternative approach to treat
all types of TTR-related amyloidosis. We completed a Phase 1 study evaluating the safety and activity of
ISIS-TTR
Rx
in healthy volunteers. In this study, ISIS-TTR
Rx
produced rapid, dose-dependent reductions in
plasma TTR protein with an average of 75 percent reduction in TTR protein, with some subjects achieving
approximately 90 percent reduction. In addition, there were several subjects that reached TTR protein levels that
were below the limit of assay detection. Subjects treated with ISIS-TTR
Rx
generally tolerated the drug well.
In February 2013, we initiated a randomized, double-blind, placebo-controlled 15-month Phase 3 study of
ISIS-TTR
Rx
in patients with FAP. In this study, we are evaluating the efficacy of ISIS-TTR
Rx
by measuring
neurological dysfunction and quality of life in patients with FAP. We already have patients who have completed
all fifteen months of treatment and are currently receiving ISIS-TTR
Rx
in an open-label extension study. We plan
to report data in 2017. Our partner, GSK, also plans to evaluate ISIS-TTR
Rx
in patients with FAC and is in the
planning stages of a Phase 3 study for this indication.
ISIS-SMN
Rx
—ISIS-SMN
Rx
is an antisense drug we discovered in collaboration with Dr. Adrian R. Krainer
at Cold Spring Harbor Laboratory. We designed ISIS-SMN
Rx
to treat SMA, a severe motor-neuron disease that is
the leading genetic cause of infant mortality. SMAaffects approximately 30,000 to 35,000 patients in the United
States, Europe and Japan. One in 50 people, approximately six million people in the United States, carry the
gene mutation that causes SMA. Carriers experience no symptoms and do not develop the disease. When both
parents are carriers, however, there is a one in four chance that their child will have SMA. SMA is caused by a
loss of, or defect in, the survival motor neuron 1, or SMN1, gene leading to a decrease in the protein, survival
motor 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 severity of SMAcorrelates with the amount of SMN
protein. Infants with Type I SMA, the most severe life-threatening form, produce very little SMN protein and
have a significantly shortened life expectancy. Children with Type II and Type III SMAhave greater amounts of
SMN protein and have less severe, but still life-altering, forms of SMA. The FDAgranted Orphan Drug
Designation with Fast Track Status to ISIS-SMN
Rx
for the treatment of patients with SMA.
In January 2012, we and Biogen Idec entered into a preferred partner alliance that provides Biogen Idec an
option to develop and commercialize ISIS-SMN
Rx
. We designed ISIS-SMN
Rx
to potentially treat all types of
childhood SMAby altering the splicing of a closely related gene, SMN2, which leads to the increased production
of fully functional SMN protein. We developed a biomarker assay to measure levels of SMN protein in the
cerebral spinal fluid of children and infants with SMA. In February 2014, we reported the first set of data using
this biomarker assay. Using this assay, we observed dose-dependent increases in SMN protein levels in children
with SMA treated with ISIS-SMN
Rx
from both the single- and multiple-dose studies. In the single-dose study,
SMN protein levels more than doubled in the two highest dose cohorts, 6 mg and 9 mg, with average increases
of approximately 120 percent and 160 percent compared to baseline, respectively, approximately nine to
14 months after dosing. Similarly, in the multiple-dose study, we observed substantial increases in SMN protein
levels in the 9 mg cohort of 115 percent compared to baseline approximately three months after the first dose. In
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