Isis Pharmaceuticals to Reinitiate Development of ISIS 2302 in Crohn's Disease
Final Analysis of Clinical Trial Shows Response to Drug In
Patients With Higher Levels of Exposure
CARLSBAD, Calif., Oct. 4 /PRNewswire/ -- Isis Pharmaceuticals, Inc. ("Isis") (Nasdaq: ISIP) announced today that it will reinitiate development of its antisense ICAM-1 inhibitor, ISIS 2302 in Crohn's disease. A recently completed analysis of the randomized trial indicates that those patients who received higher exposure to ISIS 2302 were more likely to experience complete clinical remission, the primary endpoint of the study. Patients in complete clinical remission were completely off steroids and symptom-free. The analysis showed that patients' exposure to drug varied based on gender and weight. Isis is planning additional clinical studies in Crohn's patients using higher doses of ISIS 2302 to reproduce the drug exposure levels that correlated with higher response rates in the analysis. Data from the trial analysis were presented today by Dr. Bruce Yacyshyn, Associate Professor, Division of Gastroenterology and Medical Microbiology and Immunology, University of Alberta at a medical meeting in Freiburg, Germany.
In the analysis, the response rate of patients exposed to higher levels of ISIS 2302 was 38%, compared to a 20% response rate for patients receiving placebo. This difference in response was statistically significant (p < 0.03).
"The correlation between exposure to ISIS 2302 and response in this trial is impressive, and I believe development of ISIS 2302 in Crohn's disease should certainly be pursued," said Stephen B. Hanauer, M.D., Professor of Medicine and Clinical Pharmacology and Director, Section of Gastroenterology and Nutrition, University of Chicago Medical Center. "There is still tremendous need for improved therapies to treat patients with Crohn's disease. ISIS 2302 inhibits a novel target, ICAM-1, by a novel mechanism, antisense. This unique approach has the potential to offer important benefits to patients, such as improved safety and prolonged duration of effect." Dr. Hanauer was one of several independent gastroenterology experts that reviewed the data as part of Isis' evaluation of this analysis.
Patient's Exposure to Drug Varied
The data from the randomized trial in Crohn's were analyzed in a population pharmacokinetic (population PK) study, a well-accepted technique that assesses the impact of drug exposure on drug safety and efficacy. The study measured total concentration of drug in plasma over time as an index of patients' total exposure to drug. Two of the factors analyzed, body weight and gender, were associated with patient-to-patient variability in drug exposure. Even though all patients received a 2 mg/kg dose of ISIS 2302, the analysis showed that heavier people and females received higher exposure to ISIS 2302 than lighter people and males, respectively. This trend provides a basis for understanding the difference in response rates from the first half to the second half of the randomized clinical trial. Patients enrolled in the first half of the trial tended to be heavier and more predominantly female than those in the second half, and therefore achieved more effective drug exposure.
Consistent Evidence that Higher Exposure Increases Response
A key conclusion of the analysis was that the greater a patient's exposure to ISIS 2302, the greater the likelihood of response to treatment. This trend was consistently demonstrated in every measurement of patient improvement: complete clinical remission, disease severity, quality of life and duration of effect.
-- Increased Rate of Complete Clinical Remission
The relationship between complete clinical remission rate and
exposure levels was evaluated in two different ways: on the basis of
cumulative exposure to drug, which is a calculation of total exposure
over time, and on the basis of a single exposure to drug. In both
cases, increased exposure predicted increased response. The complete
clinical remission rate of patients with the highest cumulative
exposure levels of ISIS 2302 was 38% compared to a response rate of
20% of patients receiving placebo. This difference in response rates
was statistically significant (p < 0.03). The trend toward increased
response at higher single-dose exposure levels was also statistically
significant (p < 0.01).
-- Improvement in Disease Severity
The impact of ISIS 2302 on patients' disease severity was measured
using the Crohn's Disease Activity Index (CDAI). The analysis showed
that as exposure to ISIS 2302 increased, the patients' CDAI score
decreased, indicating that disease severity had lessened. This trend
was significant (p < 0.03).
-- Improvement in Quality of Life
Similarly, patients' quality of life was measured using the
Inflammatory Bowel Disease Quotient (IBDQ). In this case IBDQ scores
increased with increased exposure to ISIS 2302, suggesting that
disease had improved. The trend was significant (p < 0.05).
-- Improvement in Duration of Remission
Duration of remission also increased as exposure to ISIS 2302
increased. Responders in the highest exposure groups experienced
median duration of remission well in excess of 6 months.
Dosing Information Gained from Effective Exposure Levels
Importantly, the analysis consistently indicates that a minimum exposure level is necessary to achieve significant response rates. The dose of 2mg/kg used in the clinical trial appears to have been insufficient for most patients to reach effective drug exposure levels. The information from this analysis can be directly used to calculate doses that should provide adequate exposure levels to increase the likelihood for each patient to benefit from therapy. This insight will guide the determination of dosages used in additional clinical trials of ISIS 2302 in Crohn's disease.
"This analysis provides substantial evidence of activity of ISIS 2302 in patients with Crohn's disease that are exposed to adequate levels of drug," said Bruce R. Yacyshyn, Associate Professor, Division of Gastroenterology and Medical Microbiology and Immunology, University of Alberta. "The consistency with which every outcome measure increased as exposure increased is compelling. Identification of the effective exposure level needed to produce response provides clear direction about dosages that are more likely to be effective in future clinical trials." Dr. Yacyshyn's presentation of the analysis today was part of Falk Symposium #119 Immunosuppression in Chronic Inflammatory Bowel Disease -- Standards, New Development and Future Trends. These data are being prepared for submission to a peer-reviewed journal.
"We are developing plans to advance ISIS 2302 into Phase III trials in Crohn's disease," said Stanley T. Crooke, M.D., Ph.D., Isis' Chairman and CEO. "While it's clear that additional work is required before we fully understand the value of ISIS 2302 in Crohn's and its commercial potential, this analysis provides further validation that first-generation antisense drugs can be of value to patients in the diseases that we have targeted. The data add to the extensive body of evidence of the utility of antisense that we've generated in tissue culture, in animals and in the clinic. The commercialization of Vitravene(TM) (fomivirsen) and data from clinical studies of both ISIS 3521 and ISIS 5132 in cancer and ISIS 2302 in earlier Crohn's studies all support antisense as an important advance for drug discovery and development.
"With the addition of ISIS 2302 in Crohn's, we now have eleven products in development," added Dr. Crooke. "This robust pipeline is one of several ways we are exploiting antisense to generate value. We are fueling our own research and generating revenue through our GeneTrove(TM) functional genomics division, and we are leveraging our patent estate to generate licensing revenue. This combination of assets demonstrates Isis' strength as a fully-integrated, genomics-based biotechnology company. Our technology-rich position is further enhanced by our Ibis Therapeutics(TM) division, which represents a second drug discovery platform that Isis has pioneered. In addition, we are reasonably well-resourced financially, with $126 million in cash at the end of second quarter. We are very pleased with the progress we are making scientifically and in the clinic, and we are committed to achieving our goals in order to maximize shareholder value."
ISIS 2302 is an antisense inhibitor of intercellular adhesion molecule-1 (ICAM-1), a molecule that plays a central role in inflammation. Phase II trials of a topical formulation ISIS 2302 for psoriasis and an enema formulation for ulcerative colitis are currently on-going.
The randomized trial in Crohn's patients was a 300-patient multi-center, randomized, double-blinded trial that compared the effects of two weeks and four weeks of treatment with ISIS 2302 to placebo. A dose of 2mg/kg was used. Patients enrolled had moderately active Crohn's disease (CDAI 200-350) and were steroid dependent (10-40 mg/day of prednisone or equivalent). The combined primary clinical endpoint was complete clinical remission, defined as a CDAI score of 150 or lower, and complete steroid withdrawal.
Isis will conduct a live webcast conference call to discuss this analysis on Wednesday, October 4 at 11:00 am Eastern time. To participate over the internet go to www.streetfusion.com. A replay of the webcast will be available at this address for up to 90 days.
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(TM) (fomivirsen), to treat CMV-induced retinitis in AIDS patients. In addition, Isis has 11 products in its development pipeline, six of which are in Phase II human clinical trials. Isis has a broad and proprietary patent estate of nearly 700 issued and allowed patents worldwide. Isis' GeneTrove(TM) division uses antisense to assist pharmaceutical industry partners in validating and prioritizing potential gene targets through customized services and access to an extensive gene function database. Ibis Therapeutics(TM) is a division focused on the discovery of small molecule drugs that bind to RNA.
This press release contains forward-looking statements pertaining to Isis Pharmaceuticals, Inc.'s drug discovery and development activities. Such statements are subject to certain risk factors and uncertainties, particularly those inherent in the process of discovering, developing and commercializing drugs that can be proven to be safe and effective for use as human therapeutics and the endeavor of building a business around such potential products. 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. Factors that could cause or contribute to such differences include, but are not limited to, those described in Isis' Annual Report on Form 10-K for the year ended December 31, 1999, which is on file with the U.S. Securities Exchange Commission.
Vitravene(TM) is a trademark of Novartis AG. GeneTrove(TM) and Ibis Therapeutics(TM) are trademarks of Isis Pharmaceuticals, Inc.
SOURCE Isis Pharmaceuticals, Inc.
CO: Isis Pharmaceuticals, Inc.
ST: California
IN: MTC HEA
SU:
10/04/2000 07:01 EDT prnewswire.com |
