Cell Pathways' CP461 Markedly Reduced Disease Symptoms in Canine Model of Refractory Inflammatory Bowel Disease.
HORSHAM, Pa.--(BW HealthWire)--May 21, 2002
Drug Induces Selective Apoptosis in Activated Macrophages,
Reducing Inflammatory Modulator that Plays Key Role in the Disease
New research reported today at the American Gastroenterology Association meeting suggests that Cell Pathways' (Nasdaq:CLPA) investigational oral drug CP461 may have potential as a treatment for inflammatory bowel disease (IBD) in addition to its previously reported anticancer activity. Seven dogs with a history of chronic and refractory IBD lasting six months to 3.5 years who had failed to respond to conventional therapies were selected for the study. The clinical signs of IBD started to resolve by day 10 after treatment, and 86% of the dogs were free of symptoms by day 30.
In addition, tissue samples surgically obtained from one of the dogs before and after treatment showed marked improvement of the diseased intestinal tract after treatment with CP461. In particular, CP461 reduced the number of activated macrophages and lymphocytes, types of white blood cells involved in inflammation, and the morphology of the intestinal tract had returned to normal after treatment. In studies of diseased canine and human tissues, high levels of cyclic GMP phosphodiesterases (cGMP PDE) of the PDE2 and PDE5 gene families have been detected (both molecular targets for CP461) in activated macrophages associated with IBD. These results are consistent with the demonstration that CP461 has a potent ability to trigger apoptosis (programmed cell death) in activated macrophages, which play a central role in IBD. These cells produce chemical modulators of inflammation -- cytokines such as tissue necrosis factor-alpha (TNF(alpha)) -- that cause intestinal inflammation and damage.
"Canines are naturally subject to IBD that appears to be similar to the disease in humans, making dogs an excellent model for the study of potential new treatments for this condition," said Hector Alila, D.V.M., Ph.D., vice president, product development. "Current treatments for IBD have limited effectiveness and/or toxicity. Studies to date indicate that CP461, an oral drug, is generally well tolerated. Furthermore, it appears to act by targeting cells (activated macrophages) that are the source of harmful cytokines such as TNF(alpha). On the basis of these intriguing preclinical results, we are planning to initiate a human clinical trial of CP461 in inflammatory bowel disease later this year."
CP461 Drug Target Demonstrated
The researchers first showed that human intestinal biopsy samples from patients with confirmed IBD contained tissue-activated macrophages with high levels of PDE2 and PDE5, two cellular targets of CP461 and Cell Pathways' other selective apoptotic antineoplastic drugs (SAANDs). Such macrophages are known to release TNF(alpha), an immune modulator that plays a central role in IBD. The researchers then demonstrated the ability of CP461 to induce apoptosis and inhibit TNF(alpha) in a human macrophage cell line. They found that treatment of the cells with 1(mu)M (micromolar) CP461 (the levels that can be achieved in bloodstream of patients) for 24 hours increased apoptosis rates by 64% in the cells and reduced production of TNF(alpha) by 23%.
"Based on these findings, we hypothesized that using CP461 to selectively induce apoptosis in tissue-activated macrophages might provide a novel approach to the treatment of IBD," said Cell Pathways' scientist, Keith Earle, D.V.M., who presented the research findings.
In collaboration with Linda J.M. Tintle, D.V.M, of the Wurtsboro Veterinary Clinic in Wurtsboro, N.Y., the researchers treated seven companion dogs having a history of IBD refractory to conventional therapies (including steroids, antibiotics and dietary management) with CP461. The dogs received either 400 mg or 800 mg of oral CP461 twice daily for 60 consecutive days, followed by a 30-day recovery period. Within 10 days of starting treatment, all dogs ceased their vomiting, diarrhea and weight loss. By day 30, 86% of the dogs were free of symptoms. There was a recurrence of symptomatic disease following cessation of treatment. Subsequently, four of the dogs were retreated with 400 mg or 800 mg twice daily for 30 days, followed by a maintenance dose of 100 mg or 200 mg twice daily for 30 days. Three of the four dogs responded to therapy and were symptomatically normal throughout the treatment period.
Intestinal biopsies obtained from one dog before treatment showed high levels of PDE2 and PDE5 in the activated macrophages. These macrophages were greatly reduced in biopsies from the same animal and histopathological improvement was obtained after treatment with CP461. Correlative studies performed with archived human intestinal biopsies also showed elevated levels of PDE2 and PDE5 in diseased IBD tissues but not in normal tissues, similar to the findings in the dogs.
About Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a collective term for a group of inflammatory diseases of the gastrointestinal tract. In humans, IBD is generally divided into two major types: ulcerative colitis, which affects only the colon, and Crohn's disease, which can affect any part of the digestive tract. Both diseases are characterized by an abnormal immune response in the gastrointestinal system that causes uncontrolled inflammation. While both diseases share the common symptoms of crampy abdominal pain and diarrhea, other significant differences between the two may include the sites affected, treatment, prognosis and complications. Crohn's disease is associated with excessive infiltration of inflammatory and immune cells that are resistant to apoptosis. These cells produce cytokines such as TNF(alpha), which contribute to chronic intestinal inflammation and tissue damage. Current treatments have limited effectiveness and/or toxicity. Physicians and patients agree there is great need for new agents to treat IBD.
According to National Institutes of Health statistics, the incidence of Crohn's disease in the United States is 7 people per 100,000 and overall, 300,000 to 500,000 people suffer from this disease. Similarly, the NIH states the incidence of ulcerative colitis is 10-15 people out of 100,000.
CP461 is a second-generation SAAND, a class of orally active compounds discovered and under development by Cell Pathways, Inc. SAANDs selectively trigger apoptosis in abnormal cells by inhibiting certain cGMP PDE that company scientists and collaborators have shown to be over-expressed in a variety of tumor types and in activated macrophages associated with IBD. This cGMP PDE inhibition leads to activation of another intracellular signaling molecule, protein kinase G, triggering a cascade of downstream events leading to apoptosis. Cell Pathways is currently conducting Phase IIa clinical trials of CP461 in a variety of cancers including chronic lymphocytic leukemia, hormone-refractory prostate cancer, and advanced kidney cancer.
About Cell Pathways
Cell Pathways, Inc., headquartered in Horsham, Pa., is a development stage pharmaceutical company focused on the research and development of novel and unique medications to treat and prevent cancer and to treat certain inflammatory diseases. The company additionally markets and sells oncology-related products made by others. The company's initial drug candidates in clinical development are Aptosyn(R) (exisulind) and CP461. For additional information on Cell Pathways, Inc., visit the Company's web site at http://www.cellpathways.com.
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|Comment:||Cell Pathways' CP461 Markedly Reduced Disease Symptoms in Canine Model of Refractory Inflammatory Bowel Disease.|
|Date:||May 21, 2002|
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