Isis Pharmaceuticals Initiates Phase II Clinical Trial of ISIS 104838, A TNF-Alpha Inhibitor, in
`Rheumatoid Arthritis
`
`March 13, 2002
`
`CARLSBAD, Calif., March 13 /PRNewswire-FirstCall/ -- Isis Pharmaceuticals, Inc., (Nasdaq: ISIS) announced today it has initiated a Phase II clinical
`trial of ISIS 104838, an antisense inhibitor of tumor necrosis factor-alpha (TNF-alpha), in rheumatoid arthritis (RA). The Phase II clinical trial will
`evaluate the safety and efficacy of ISIS 104838 in RA when administered by subcutaneous injection (SQ) for three months. This is the second Phase II
`study of ISIS 104838 in RA currently in progress. TNF-alpha is a naturally occurring cytokine that is involved in the development and progression of
`many inflammatory diseases, including RA.
`
`The double-masked, placebo-controlled, randomized Phase II study is planned to enroll 160 people with RA at 25 sites in the U.S. and Canada. Three
`dosing regimens will be examined in this study: ISIS 104838 injections twice a week, once a week or once every other week. The primary endpoint in
`the study is improvement in American College of Rheumatology (ACR) response criteria, which measures improvement in patient- and professional-
`reported disease severity and activity.
`
`"We are pleased to begin the second study of ISIS 104838 in people with rheumatoid arthritis, and to move forward with the clinical development of our
`new generation of antisense drugs. The initial Phase II trial, which began last November, is studying ISIS 104838 drug concentrations in tissue and
`blood as well as the drug's ability to reduce TNF-alpha levels. This new trial will be the first to provide efficacy information about ISIS 104838 in RA.
`We will use the combined results from the two studies to direct our future development plans with this drug," said F. Andrew Dorr, M.D., Isis Vice
`President and Chief Medical Officer.
`
`Isis' first Phase II clinical trial of ISIS 104838 is evaluating the biological effect of TNF-alpha inhibition by ISIS 104838 in 20 RA patients over a
`four-week treatment period. Oral formulations of ISIS 104838 are being developed in parallel by Orasense™ Ltd., a joint venture between Isis and
`Elan Corporation plc.
`
`ISIS 104838 is a product of Isis' proprietary second-generation chemistry called 2'-O-methoxyethyl. Phase I trials of intravenous infusion and SQ
`administration of ISIS 104838 demonstrated enhanced tolerability, duration of effect and dosing convenience compared with first-generation drugs. In
`June 2001, Isis initiated a Phase II clinical trial of topical ISIS 104838 in psoriasis. Currently, Isis has six second-generation products in its
`development pipeline to treat RA, diabetes, diabetic retinopathy, psoriasis, multiple sclerosis and cancer.
`
`According to the Arthritis Foundation, RA affects 2.1 million Americans, predominately women. RA is a systemic disease that affects the entire body
`and is one of the most common forms of arthritis. RA is characterized by the inflammation of the membrane lining in the joint, or synovium, which
`causes pain, stiffness, warmth, redness and swelling. The synovium can invade locally and causes damage to bone and cartilage. Inflammatory cells
`release enzymes that may digest bone and cartilage. The involved joint can lose its shape and alignment, resulting in pain and loss of movement.
`
`Isis Pharmaceuticals, Inc. is exploiting its expertise in RNA to discover and develop novel human therapeutic drugs. The company has commercialized
`its first product, Vitravene® (fomivirsen), to treat CMV-induced retinitis in AIDS patients. In addition, Isis has 12 products in its development pipeline,
`with two in late-stage development and six in Phase II human clinical trials. LY900003 (ISIS 3521), an inhibitor of PKC-alpha, is in Phase III trials for
`non-small cell lung cancer, and alicaforsen (ISIS 2302), an ICAM-1 inhibitor, is in Phase III human clinical trials for Crohn's disease. Isis has a broad
`patent estate, as the owner or exclusive licensee of nearly 900 issued patents worldwide. Isis' GeneTrove™ division uses antisense to assist
`pharmaceutical industry partners in validating and prioritizing potential gene targets through customized services. Ibis Therapeutics™ is a division
`focused on the discovery of small molecule drugs that bind to RNA.
`
`This press release contains forward-looking statements concerning the development and potential of the investigational compound ISIS 104838 in the
`treatment of rheumatoid arthritis. Any statement describing an expectation, intention or belief of the company is a forward-looking statement and
`should be considered an at-risk statement. Such statements are subject to 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 financing such activities. Actual
`results could differ materially from those projected in this release. As a result, you are cautioned not to rely on these forward-looking statements.
`These and other risks concerning Isis' research and development programs are described in additional detail on Form 10Q, for the period ended
`September 30, 2001, which is on file with the U.S. Securities and Exchange Commission, copies of which are available from the company.
`
`Vitravene® is a registered trademark of Novartis AG.
`
`GeneTrove™ and Ibis Therapeutics™ are trademarks of Isis Pharmaceuticals, Inc.
`
` Orasense™ is a trademark of Orasense, Ltd.(cid:10)
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`SOURCE Isis Pharmaceuticals, Inc.
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`Web site: http: //www.isip.com
`CONTACT: Kristina Peterson of Isis Pharmaceuticals, Inc., +1-760-603-2521
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