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Isis Highlights New Data on Antisense Drugs to Treat Type 2 Diabetes and Obesity at ADA Scientific Sessions
In the oral presentation titled "ISIS 388626, an SGLT2 Antisense Drug, Causes Robust and Sustained Glucosuria in Multiple Species and is Safe and Well-Tolerated," Dr. Sanjay Bhanot highlighted data that demonstrated that antisense reduction of SGLT2, a key transporter involved in glucose re-absorption in the kidney, produced the following results in preclinical models:
-- Dose-dependent reduction in kidney levels of SGLT2 with >75% reduction
at the highest dose accompanied by a significant increase (>100-fold)
in glucose excretion in the urine in multiple species including
monkeys
-- Secondary improvements in glucose tolerance and insulin sensitivity
-- Significant reduction in plasma glucose levels in extremely
hyperglycemic animals
-- No harmful effects such as low blood glucose levels (hypoglycemia) or
detrimental changes in kidney function with 3-6 month exposure in
normal or diabetic animals.
"Our preclinical research during the past year on ISIS-SGLT2Rx extends
previous findings and demonstrates potent and sustained reduction of blood
glucose levels with good safety and tolerability in multiple animal models
including non-human primates. Collectively, the data suggest that
ISIS-SGLT2Rx could result in sustained and significant reductions in blood
glucose levels in diabetic patients and could be used as an infrequent
injectable drug to help control blood sugar. This year, we have initiated our
first clinical trial on ISIS-SGLT2Rx that will not only assess the safety of
the drug in healthy volunteers, but may also provide us with information on
the activity of the drug by measuring the effect of ISIS-SGLT2Rx on glucose
excretion in urine. We are excited to continue to move this drug forward
through development," said Sanjay Bhanot, M.D., Ph.D., Vice President of
Metabolic Disorders and Head of Translational Medicine at
Isis scientists presented new data demonstrating that antisense reduction of retinal binding protein 4 (RBP4) caused significant improvements in insulin sensitivity with associated improvement in cardiac glucose metabolism. These data suggest that RBP4 could be an important new therapeutic target for type 2 diabetes and associated cardiac disease.
In addition to new data demonstrating the ability of antisense drugs to significantly improve insulin sensitivity in diabetic animals, Isis also presented data from its obesity drug discovery program. In an oral presentation, Isis reported that antisense reduction of fibroblast growth factor receptor 4 (FGFR4) lowered adiposity and improved insulin sensitivity in mice, indicating that FGFR4 plays a role in the regulation of energy expenditure and adiposity. Selective inhibition of FGFR4 with antisense drugs in peripheral tissues could be a unique therapeutic approach for the treatment of obesity and related metabolic disorders.
"We are looking forward to expanding our metabolic disease pipeline by adding antisense drugs to treat obesity, an area with great unmet need where our peripherally acting drugs could have significant therapeutic utility without the potential for central nervous system toxicities that plague many centrally acting anti-obesity drugs," continued Dr. Bhanot. "Obesity is just one example of the many therapeutic areas that are amendable to our antisense drug discovery efforts. We continue to expand our discovery efforts and broaden our drug pipeline to address new diseases within our core therapeutic programs in cardiovascular, metabolic and severe neurodegenerative diseases and cancer."
Including presentations highlighting SGLT2 and FGFR4, Isis and its collaborators presented a total of eight presentations (including three oral talks and two late-breaking posters) at this year's ADA conference. The additional presentations highlighted antisense inhibitors to a number of metabolic targets in a variety of animal species that reduced mRNA target levels in specific tissues and provided therapeutic benefit such as improved insulin sensitivity, reduced fat mass and body weight in various models of disease. Complete abstracts for the presentations can be found on the ADA Web site at www.diabetes.org.
ISIS 388626, an SGLT2 Antisense Drug, Causes Robust and Sustained
Glucosuria in Multiple Species and Is Safe and Well-Tolerated (Oral
Presentation)
Authors: S. Bhanot, S.F. Murray , S.L. Booten , K. Chakravarty, T. Zanardi,
S. Henry, L.M. Watts , E.V. Wancewicz, A. Siwkowski, B.P. Monia.
Antisense Reduction of FGFR4 Gene Expression Lowers Body Weight and
Adiposity and Improves Insulin Sensitivity in Rodents (Oral Presentation)
Authors: X.X. Yu , L.M. Watts , P. Manchem, S.L. Booten , B.P. Monia, S.
Bhanot.
Antisense Inhibition of cAMP Response Element Binding Protein (CREB)
Expression Lowers Plasma Glucose and Lipids in Diabetic Rodents (Oral
Presentation)
Authors: S.F. Murray , S.L. Booten , L.M. Watts , B.P. Monia, S. Bhanot.
A Newly Identified Role of Nuclear Receptor Corepressor, SMRT (Silencing
Mediator of Retinoid and Thyroid) in Improving Hyperglycemia and Insulin
Sensitivity in Obese and Diabetic Mice (Late-Breaking Poster)
Authors: S.K. Pandey , S.F. Murray , S. Guo, L.M. Watts , S.L. Booten , A.
Siwkowski, D. Witchell, P. Manchem, S. Bhanot, B.P. Monia.
Inhibition of Transthyretin Expression by Antisense Oligonucleotides
Lowers RBP4 Levels, Improves Insulin Sensitivity and Increases Heart
Glucose Uptake in Diet-Induced Obese Mice (Late-Breaking Poster)
Authors: P. Manchem, S.F. Murray , S.L. Booten , X.X. Yu , L.M. Watts , B.P.
Monia, S. Bhanot.
Antisense Reduction of RBP4 Expression Causes a Marked Improvement in
Hepatic and Peripheral Insulin Sensitivity and Improves Cardiac Glucose
Uptake in Diet-Induced Obese Mice
Authors: P. Manchem, X.X. Yu , S.L. Booten , L.M. Watts , S.F. Murray , B.P.
Monia, S. Bhanot.
Knockdown of Carbohydrate Response Element Binding Protein (ChREBP) in
Liver Protects Against Fructose Induced Hyperlipidemia and Insulin
Resistance
Authors: D.M. Erion , J.J. Hsiao , S. Yonemitsu, R. Stark, J. Dong, Y.
Nagai, T. May, M. Kahn, X.X. Yu , S.F. Murray , S. Bhanot, B.P. Monia, G.W.
Cline, V.T. Samuel , G.I. Shulman .
Matrix Metalloproteinase-9: Association With Insulin Resistance and
Obesity and PKC-alpha Mediated Regulation by Pioglitazone
Authors: R. Unal, A. Yao-Borengasser, V. Varma, N. Rasouli, B. Phanavanh,
C. Labbate, B.P. Monia, P.A. Kern , G. Ranganathan.
ABOUT
Isis is exploiting its expertise in RNA to discover and develop novel
drugs for its product pipeline and for its partners. The Company has
successfully commercialized the world's first antisense drug and has 19 drugs
in development. Isis' drug development programs are focused on treating
cardiovascular, metabolic and severe neurodegenerative diseases and cancer.
Isis' partners are developing antisense drugs invented by Isis to treat a wide
variety of diseases. Isis and
This press release includes forward-looking statements regarding Isis'
business, its drug discovery and development pipeline, and the therapeutic
potential of antisense drugs for the treatment of cardiovascular and metabolic
diseases. Any statement describing Isis' goals, expectations, financial or
other projections, intentions or beliefs is a forward-looking statement and
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certain risks and uncertainties, particularly those inherent in the process of
discovering, developing and commercializing drugs that are safe and effective
for use as human therapeutics, and in the endeavor of building a business
around such products. Isis' forward-looking statements also involve
assumptions that, if they never materialize or prove correct, could cause its
results to differ materially from those expressed or implied by such
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to rely on these forward-looking statements. These and other risks concerning
Isis' programs are described in additional detail in Isis' annual report on
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SOURCEIsis Pharmaceuticals, Inc. -0-06/09/2009 /CONTACT: Kristina Lemonidis, Director, Investor Relations, +1-760-603-2490, orAmy Blackley , Ph.D., Assistant Director, Corporate Communications, +1-760-603-2772, both ofIsis Pharmaceuticals, Inc. / /Web Site: http://www.isispharm.com / (ISIS) CO:Isis Pharmaceuticals, Inc. ST:Louisiana ,California IN: HEA PHA MTC SU: TRI PR -- LA29463 -- 261306/09/2009 07:00 EDT http://www.prnewswire.com