Thanks for your response j.d.robbins.
Here is a press release that appeared today on most news services:
ISIS DEMONSTRATES ATTRACTIVE PHARMACOKINETICS OF SECOND AND THIRD
GENERATION ANTISENSE COMPOUNDS IN ANIMALS
CARLSBAD, Calif., May 16 /PRNewswire/ -- Isis Pharmaceuticals (Nasdaq: ISIP) announces results of a comprehensive pharmacokinetic analysis of several second and third generation antisense compounds. These novel compounds are based on the company's proprietary chemistries which enable Isis to design novel antisense compounds with a wide range of attractive drug properties and represent significantly enhanced therapeutic potential over first generation compounds. The article, published in the May issue of the Journal of Pharmacology and Experimental Therapeutics, is the first published study of the comparative advantages of different antisense oligonucleotides and the most extensive demonstration in animals of the use of medicinal chemistry to create and optimize selected properties of antisense drugs in order to optimize therapeutic benefit.
The purpose of this study, and studies to be reported in later papers, was to better understand the value of various chemical modifications of antisense compounds by comparing the effects of these modifications in animals on the pharmacokinetic, pharmacological and toxicological properties of the compounds. These properties include the binding affinity of the modified antisense compounds for their target mRNAs, their ability to reduce mRNA levels and inhibit protein production, and their ability to reduce side effects. Five analogs of a first generation phosphorothioate antisense oligonucleotide were used in the study, each representing a novel chemical modification. The biophysical (stability, lipophilicity) and pharmacokinetic (absorption, distribution and metabolism) properties of these analogs were characterized in mice. The first generation compound upon which the analogs were modeled was ISIS 3082, a potent, selective inhibitor of human intercellular adhesion molecule-1 (ICAM-1), which has shown activity in a number of animal models of inflammatory disease. ISIS 3082 is a mouse analog of ISIS 2302, an inhibitor of human ICAM-1 which is currently in Phase II clinical trials to treat a broad range of inflammatory diseases.
The conclusions of the study were that different chemical modifications of antisense compounds produced, in some cases, significantly different distribution of the compounds to different organs and produced significant differences in stability when compared to the parent ISIS 3082 compound. For example, one modification resulted in significantly greater distribution of an antisense compound in kidney, while another exhibited similar distribution to liver, suggesting that such modifications may permit more tissue-selective targeting of antisense compounds to these organs to gain therapeutic effect. One modification resulted in a considerable increase in stability in specific tissues suggesting the possibility of very infrequent dosing (e.g., once per week) and potential oral bioavailability. In summary, the study presents extensive evidence of the therapeutic versatility of different generations of antisense compounds.
"This paper is the first comprehensive study designed to determine in vivo the activity of new generations of antisense drugs in specific organs in terms of their potency, dosing schedule, safety and potential therapeutic utility," said Stanley T. Crooke, M.D., Ph.D., Isis Chairman and Chief Executive Officer and first author of this paper. "Since its inception, Isis has synthesized over 10,000 antisense compounds and used our expertise in medicinal chemistry to develop hundreds of novel, proprietary chemical modifications designed to enhance the drug properties of these compounds. This kind of rigorous scientific endeavor will enable us potentially to select optimal combinations of drug behaviors for use in creating safer and more potent antisense drugs that will be both therapeutically and commercially valuable."
The paper, entitled, "Pharmacokinetic Properties of Several Novel Oligonucleotide Analogs in Mice" was authored by Stanley T. Crooke, Mark J. Graham, Joan E. Zuckerman, Douglas Brooks, Boyd S. Conklin, Lendell L. Cummins, Michael J. Greig, Charles J. Guinosso, Douglas Kornbrust, Mutiah Manoharan, Henry M. Sasmor, Thomas Schleich, Kathleen L. Tivel and Richard H. Griffey. Douglas Brooks and Thomas Schleich are from the University of California at Santa Cruz, and Douglas Kornbrust is from Sierra Biomedical, Inc. All other authors are from Isis Pharmaceuticals.
This press release contains forward-looking statements concerning the therapeutic and commercial potential of Isis' antisense technology and compounds based on that technology. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that can be safe and effective for use as human therapeutics. Actual results could differ materially from those projected in this release. As a result, the reader is cautioned not to rely on these forward-looking statements. These and other risks are described in additional detail in Isis' Annual Report on Form 10-K for the year ended December 31, 1995, which is on file with the U.S. Securities Exchange Commission, a copy of which is available from the company.
Isis Pharmaceuticals, based in northern San Diego County, is engaged in the discovery and development of novel human therapeutic compounds. Isis has four compounds in human clinical trials: ISIS 2922, to treat CMV-induced retinitis in AIDS patients, is in Phase III clinical trials; ISIS 2302, an inhibitor of ICAM-1, is in Phase II clinical trials for renal transplant rejection, rheumatoid arthritis, psoriasis, Crohn's disease and ulcerative colitis; and ISIS 3521/CGP 64128A and ISIS 5132/CGP69846A, both anticancer compounds, are in Phase I clinical trials. The company also has several additional compounds in preclinical development. Isis' broad medicinal chemistry and biology research programs support efforts in both antisense and combinatorial drug discovery.
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/CONTACT: Jane Green, Director, Investor Relations of Isis, 619-603-3880/
(ISIP)
CO: Isis Pharmaceuticals ST: California IN: MTC SU: |
