The safety and tolerability profile of ISIS-APOCIII
Rx
supports continued development. The most common
adverse event was injection site reactions, which were predominantly mild and typically resolved rapidly. There
were no flu-like symptoms, no treatment-related elevations in liver enzymes greater than three times the upper
limit of normal, no abnormalities in renal function and no clinically meaningful changes in other laboratory
values.
In December 2014, we published results from the Phase 2 study of ISIS-APOCIII
Rx
in patients with FCS in
the NewEngland Journal of Medicine.
We are evaluating ISIS-APOCIII
Rx
in a Phase 3 study in patients with FCS. The Phase 3 study,
APPROACH, is a randomized, double-blind, placebo-controlled 52-week study in approximately 50 patients with
FCS. In this study, we are evaluating the efficacy of ISIS-APOCIII
Rx
by measuring the percent change in fasting
triglycerides from baseline after three months of dosing. We plan to initiate a Phase 3 study in patients with
partial lipodystrophy in 2015. We are designing this study to support a regulatory filing for ISIS-APOCIII
Rx
in
patients with partial lipodystrophy. In early 2015, we initiated a second Phase 3 study, COMPASS, in patients
with triglycerides greater than 500 mg/dL. We are designing this study to provide additional clinical experience
and safety data to support our regulatory filings for FCS and partial lipodystrophy. We plan to report data from
these studies in the 2016/2017 timeframe.
ATL1103
—ATL1103 is an antisense drug designed to target the growth hormone receptor, or GHr, a
receptor that, when inhibited, reduces the level of circulating insulin-like growth factor-1, or IGF-1, produced in
the liver. IGF-1 is a hormone that contributes to various diseases, including acromegaly, an abnormal growth
disorder of organs, face, hands and feet. IGF-1 also contributes to diabetic retinopathy, a common disease of the
eye and a leading cause of blindness, diabetic nephropathy of the kidney and certain forms of cancer. In
preclinical studies, ATL1103 demonstrated significant reductions in IGF-1 levels in the blood and inhibition of
neovascularization, or new blood vessels, in the eye in a mouse retinopathy model.
Antisense Therapeutics Limited, or ATL is developingATL1103 and has completed a Phase 1 study in
healthy volunteers demonstrating that ATL1103 was safe and well tolerated. ATL has also completed a Phase 2
study of ATL1103 in patients with acromegaly. In September 2014, ATL reported results from this study showing
a statistically significant average reduction in serum IGF-I levels of 26 percent from baseline at week 14 with the
400 mg per week dose, the highest dose tested. ATL reported that ATL1103 was generally well tolerated in the
study. The most common adverse event was injection site reactions, which were predominantly mild and
typically resolved within days. ATL plans to initiate a small study at a higher dose than 400 mg per week.
ISIS-DMPK-2.5
Rx
—ISIS-DMPK-2.5
Rx
, formerly ISIS-DMPK
Rx
, is a generation 2.5 antisense drug we
designed to correct the underlying genetic defect that causes Myotonic Dystrophy Type 1, or DM1. DM1 is a
rare genetic neuromuscular disease primarily characterized by progressive muscle atrophy, weakness and
myotonia. DM1 is the most common form of muscular dystrophy in adults and affects approximately 150,000
patients in the United States, Europe and Japan. Patients with DM1 have a genetic defect in their DMPK, or
dystrophia myotonica-protein kinase, gene in which a sequence of three nucleotides repeats extensively, creating
an abnormally long RNA, which becomes toxic as it accumulates in the nucleus of cells and prevents the
production of proteins needed for normal cellular function. The number of triplet repeats increases from one
generation to the next, resulting in the possibility of more severe disease in each subsequent generation. There
are currently no disease-modifying therapies that address the disease. The FDAgranted Orphan Drug Designation
to ISIS-DMPK-2.5
Rx
for the treatment of patients with DM1.
In 2012, we and Biogen Idec entered into an alliance that provides Biogen Idec an option to develop and
commercialize ISIS-DMPK-2.5
Rx
. We designed ISIS-DMPK-2.5
Rx
to target DMPK and reduce the toxic DMPK
RNA in the cells. In preclinical studies, we showed that an antisense compound targeting the DMPKmessenger
RNA, or mRNA, entered muscle cells and significantly reduced the toxic RNA. Effective reduction of toxic
RNA led to a reversal of the disease symptoms that was sustained for up to one year after treatment in a mouse
model of DM1. By removing toxic RNA, ISIS-DMPK-2.5
Rx
could be an effective approach to treating patients
with DM1.
We are evaluating ISIS-DMPK-2.5
Rx
in a randomized, placebo-controlled, dose-escalation Phase 1/2 clinical
study in patients with DM1 and plan to report data from this study in late 2015 or early 2016.
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