Alicaforsen Significantly Improves Symptoms and Produces Durable Responses in Patients With Ulcerative Colitis

Company to Host Webcast to Review Results and Provide Additional Data Today at 7:30 AM ET CARLSBAD, Calif., Dec 2, 2004 /PRNewswire-FirstCall via COMTEX/ -- Isis Pharmaceuticals, Inc. (Nasdaq: ISIS) announced today the results of three Phase 2 studies of alicaforsen enema to treat patients with ulcerative colitis (UC). In these Phase 2 clinical trials, alicaforsen enema produced significant and long-lasting disease improvement, as measured by changes in Disease Activity Index (DAI) scores and other indicators of disease. In particular, a substantial number of patients treated with alicaforsen enema experienced mucosal healing, as well as decreases in rectal bleeding and in stool frequency; manifestations of the disease that cause considerable discomfort, inconvenience and pain to patients. In all three trials, alicaforsen enema was well-tolerated. "For clinicians, new drugs that are safe and produce long-term disease improvement are critical. The prolonged responses of UC patients treated with alicaforsen enema are impressive, lasting much longer than those observed with currently available enemas," said Philip B. Miner, Jr., M.D., Clinical Professor of Medicine at the University of Oklahoma, President and Medical Director of The Oklahoma Foundation for Digestive Research, and a clinical investigator in the Phase 2 studies. "Based on data from these trials, as well as positive data from previously reported studies, alicaforsen enema has the potential to be an important development in the treatment of UC." "We have met all of our objectives for our Phase 2 program in ulcerative colitis. We have confirmed that alicaforsen enema produces, when compared to either placebo or the enema standard of care, responses that can last six months or longer, identified a dose and schedule for Phase 3 clinical trials and established that alicaforsen enema can be a local treatment for a local disease. The durability of treatment benefit with alicaforsen enema is a key competitive advantage in the commercial profile of this drug," said Mark Wedel, M.D., J.D., Isis' Vice President of Development and Chief Medical Officer. "Our next steps will be to use the results from our broad Phase 2 experience to design effective Phase 3 clinical trials, and to discuss these data and our plans for Phase 3 clinical trials with the U.S. Food and Drug Administration." Phase 2 Clinical Trials of Alicaforsen in Ulcerative Colitis: Designed to Measure Activity and Duration of Response To support the Phase 3 development of alicaforsen enema for UC, Isis conducted four Phase 2 trials involving more than 300 UC patients. Today, the company is reporting results from the three most recent studies. The goals of these trials were to characterize the safety profile of alicaforsen enema, identify the dose and dose regimen for Phase 3 trials, and to compare the activity of alicaforsen enema to mesalamine enema, the enema standard of care for the treatment of UC. The objectives of the placebo-controlled study were to determine a dose and dose regimen for Phase 3 clinical studies and to confirm the drug's ability to produce durable responses. The primary objective of the mesalamine enema comparison study was to compare the drug's safety, efficacy and durability of response to that of mesalamine enema. The objective of the pharmacokinetics study was to determine if the drug was systemically absorbed. In addition, safety and efficacy of alicaforsen enema were also assessed. As a result of these trials, the company has selected the best performing dose and dose regimen of 240mg nightly for Phase 3 clinical trials. Key results from each study on the top performing alicaforsen enema dose of 240mg nightly are reported below: Placebo-Controlled Study Once-nightly administration of 240mg alicaforsen enema for six weeks produced greater and more durable responses, as measured by DAI, than placebo. In addition, alicaforsen enema-treated patients had improved mucosal healing, decreased rectal bleeding and decreased stool frequency. Alicaforsen enema was well-tolerated. Specifically: Based on an intent-to-treat analysis, 59% (13/22) of patients treated with 240mg alicaforsen enema achieved a response, as measured by DAI. Six months later, the end of the study, 77% (10/13) of these patients continued to respond. Patients treated with alicaforsen enema who achieved a response maintained their response, on average, for longer than six months compared to a duration of response of less than 3 months for placebo-treated patients. Alicaforsen enema-treated patients achieved a mean 51% reduction in DAI at week 18 and 50% at week 30, compared to 18% and 11% at weeks 18 and 30, respectively, for patients treated with placebo (p=0.04 and p=0.03, respectively). Disease improvement observed with alicaforsen enema was more pronounced in patients with moderate disease than in patients with mild UC. Mean improvement in DAI demonstrated strong trends in favor of the drug or statistical significance compared to placebo. The improvement was confirmed by analyses of mucosal healing, reduction in rectal bleeding, reduction in stool frequency, and by the Physician Global Assessment, the doctor's assessment of all aspects of a UC patient's health. Responses to alicaforsen enema were durable. Mesalamine Comparison Study Patients treated with 240mg alicaforsen enema nightly for six weeks achieved improvements in disease equal to or better than patients treated with mesalamine enema. Alicaforsen enema was well-tolerated. Responses in patients receiving alicaforsen enema were substantially more durable than those of mesalamine enema-treated patients. Specifically: The acute response to alicaforsen enema was comparable to that of mesalamine enema. Many patients treated with alicaforsen enema who achieved a response maintained their response for six months or longer compared to an average duration of response of less than 3 months for mesalamine enema-treated patients. Across all time points following treatment in the 54-week study, patients treated with alicaforsen enema demonstrated greater improvement in DAI than patients treated with mesalamine enema. Improvements in mucosal healing, decreases in rectal bleeding and decreases in stool frequency also demonstrated strong trends in favor of alicaforsen enema or statistical significance compared to mesalamine enema. These data confirm the benefits of alicaforsen enema, as assessed by DAI and numerous other measures. Pharmacokinetics Study: Patients receiving once nightly doses of 240mg alicaforsen enema for six weeks achieved significant improvements in DAI, demonstrated little to no systemic absorption of the drug, and achieved mucosal healing by the end of the trial. Specifically: Patients treated with 240mg alicaforsen enema experienced minimal to no systemic absorption of drug (1% of dose), demonstrating that the drug is acting locally to treat this local disease. 75% (9/12) of patients demonstrated improved DAI over the six week course of the study. 58% (7/12) of patients treated with 240mg alicaforsen enema achieved mucosal healing at week 6. Safety Summary In all three UC studies, alicaforsen was well-tolerated. There were no discontinuations due to side effects. Further, no notable difference in the overall rate of side effects between the alicaforsen enema, placebo and mesalamine enema treatment groups was observed. About the Ulcerative Colitis Phase 2 Clinical Trials About DAI DAI is a commonly used, 12-point clinical scoring system for the severity of disease in UC patients (0=lowest score; 12=highest score). In the studies reported, response was defined as a reduction in DAI of at least three points at the end of treatment. Decreases in rectal bleeding and stool frequency are important measures of the successful treatment of UC and improvement in patients' quality of life. UC is also marked by inflammation and ulceration of the colonic mucosa, or innermost lining of the large intestine, which is determined by an endoscopic evaluation of the colon. Mucosal healing, or reduction of the disease-related inflammation, is another key indicator of disease improvement. Placebo-Controlled Study In a randomized, double-masked, placebo-controlled study, 112 patients were randomized to receive one of four alicaforsen enema dose regimens: 240mg every night; 240mg every night for 10 days and then every other day dosing; 240mg every other night; and 120mg every night for 10 days and then every other day dosing, or placebo. Patients in each dose cohort received their respective enema treatments over a six week period; those who achieved a response were followed for up to six months. Patients in the trial had UC for a mean of 7.5 years. This multi-center trial took place in the U.S. and in Europe. Mesalamine Comparison Study In this randomized, double-masked, active-controlled study trial, 159 patients with mild-to-moderate left-sided colitis received either 120mg alicaforsen enema, 240mg alicaforsen enema or 4.0g mesalamine enema once nightly for six weeks. Patients who achieved a response at six weeks were followed for up to one year. Patients participating in this multi-center U.S.-based study had UC for a mean of 9.3 years and were allowed to remain on baseline oral medications for their disease. Pharmacokinetics Study: In this open-label trial, 12 patients with left-sided colitis received 240mg of alicaforsen enema once nightly for six weeks. At the end of the dosing period, patients were evaluated for drug absorption to determine the extent of systemic drug exposure. All patients in the trial presented severe mucosal inflammation upon entering the study. This trial was conducted at a single center in the U.S. About Alicaforsen Alicaforsen is an inhibitor of ICAM-1, a molecule that plays a key role in a wide range of inflammatory and autoimmune conditions. ICAM-1 influences lymphocyte function, pivotal in cell trafficking, and is over-expressed in UC. ICAM-1 is part of a molecular family (known as Cellular Adhesion Molecules, or CAMs) that can be found on the surface of virtually every cell in the body, including cells that line the inflamed gastrointestinal (GI) tract. About Ulcerative Colitis Ulcerative colitis (UC) is an inflammatory bowel disease (IBD). Approximately one million people in the U.S. and in Europe are diagnosed with UC, according to the Crohn's and Colitis Foundation of America and the European Federation of Crohn's and Ulcerative Colitis Associations (EFCCA). Although the precise cause of UC disease remains unknown, it is thought to result from inappropriate immunologic activity in the GI tract, which causes chronic inflammation. Proteins produced by immune cells in the course of inflammation damage the surrounding tissue, ulcerating and injuring the bowel. Symptoms include diarrhea, abdominal cramping, rectal bleeding, loss of appetite and weight loss. Effects can range from moderate discomfort to severe debilitation requiring hospitalization to surgical removal of portions of the colon. Isis will conduct a live webcast conference call to review these results today at 7:30 AM Eastern time. To participate over the Internet go to www.isispharm.com. A replay of the webcast will be available at this address. About Isis Pharmaceuticals, Inc. Isis Pharmaceuticals, Inc. is exploiting its expertise in RNA to discover and develop novel human therapeutic drugs for its pipeline and for its partners. The company has successfully commercialized the world's first antisense drug and has 10 antisense products in development to treat metabolic, cardiovascular, inflammatory and viral diseases, and cancer. Through its Ibis Therapeutics® program, Isis is developing a biosensor to identify infectious organisms, and is discovering small molecule drugs that bind to RNA. As an innovator in RNA-based drug discovery and development, Isis is the owner or exclusive licensee of more than 1,400 issued patents worldwide. Additional information about Isis is available at http://www.isispharm.com. This press release includes forward-looking statements regarding the development, therapeutic potential and safety of alicaforsen enema in treating ulcerative colitis. Any statement describing our goals, expectations, intentions or beliefs is a forward-looking statement and should be considered an at-risk statement, including those statements that are described as Isis' clinical goals. Such statements are subject to certain risks and uncertainties, particularly those inherent in the process of developing technology, in discovering and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such products. Actual results could differ materially from those discussed in this press 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 in Isis' Annual Report on Form 10-K for the year ended December 31, 2003, and quarterly report on Form 10-Q for the quarter ended September 30, 2004, which are on file with the U.S. Securities and Exchange Commission. Copies of these and other documents are available from the company. Ibis Therapeutics® is a registered trademark of Isis Pharmaceuticals, Inc. SOURCE Isis Pharmaceuticals Investor Relations & Corporate Communications, Kristina Peterson, or Alison Trollope, both for Isis Pharmaceuticals, 760-603-2331 http://www.isispharm.com Footer Navigation Legal and Compliance: Legal Notice Code of Ethics and Business Conduct Privacy Policy Consumer Health Data Privacy Policy Your Privacy Choices Akcea Therapeutics Information For: Medical Professionals Investors & Media Job Seekers Suppliers Explore: Our Story Our Science Our Pipeline Our Culture Our News Stay Connected: Contact Us LinkedIn X Instagram Facebook Community Guidelines ©1989 – 2026 Ionis Pharmaceuticals® is a registered trademark of Ionis Pharmaceuticals, Inc. Akcea Therapeutics® is a wholly owned subsidiary of Ionis Pharmaceuticals, Inc.

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