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CELL MEDIATORS INITIAL EFFICACY TRIALS SHOULD BE IN ACUTE INFLAMMATORY DISEASES, NOT IN COMPLEX CONDITIONS SUCH AS SEPSIS, RESEARCH EXECS SUGGEST

Executive Summary

Initial clinical trials of cell mediators, such as tumor necrosis factor receptors and interleukin-I receptor antagonists, should be conducted in acute inflammatory diseases to determine if the agents have clinical benefit, not in complex ones such as sepsis, research executives suggested at a Sept. 27-29 conference on new therapeutics for inflammation. At the conference, held in New Orleans and sponsored by Cambridge Healthtech Institute, a meeting participant asked a panel of researchers whether there are indications that would be better than sepsis to pursue in clinical trials of cell mediators given the poor results seen in sepsis trials to date, most recently in Immunex' Phase II trial of its soluble TNF receptor. Cortech Director of Inflammation and Pharmacology Eric Whalley responded: "I think sepsis is probably the most severe test" for these compounds. Immunex Director of Extramural Research Michael Widmer suggested: "I think that probably the easiest thing to try are conditions of acute inflammatory response, where you don't require long administration of these molecules." Widmer added that "the more chronic conditions such as arthritis [could be] tougher to demonstrate efficacy. So I would say, just from a practical point of view, you're almost forced to try the acute conditions first." Whalley and Widmer suggested that since sepsis is a complex condition, it may be necessary to attack it through a multifactorial approach instead of targeting a single mechanism. Intervention at multiple points also may apply to other inflammatory conditions, conference participants indicated. During his presentation on Cortech's research program, Whalley explained that the company's approach to inflammatory diseases incorporates the concept that a multifactorial approach may be the most effective one. Whalley said: "We can conclude that given the complex interactions associated with inflammatory disease, single action compounds are not likely to be" the most effective treatments. The concept of an "antisepsis cocktail" approach to treating sepsis was advocated by Roger Bone, MD, Rush-Presbyterian-St. Luke's Medical Center, in the Sept. 25, 1991 issue of the Journal of the American Medical Association ("The Pink Sheet" Sept. 30, 1991, T&G-7). Bone wrote that "the complexity" of the sepsis cascade "leads me to believe that it is unlikely that any one agent will prove to be a magic bullet. Multiple agents, perhaps tailored to individual circumstances, will most likely be needed." Bone's article reviewed endotoxins, TNF alpha and IL-1 cell mediators and the data available at the time on each in the treatment of sepsis. Immunex'trial of its soluble TNF receptor "showed the drug provided no clinical benefit" in treating sepsis, the company announced Sept. 27. The 141-patient trial compared three doses of TNF receptor to placebo and found that low-dose treated patients fared no better than placebo, while those at higher doses "had worse outcomes than the placebo group." Immunex said it believes the drug "has therapeutic potential in other disease settings." At the conference, Immunex' Widmer said early trials of TNF receptor are "in progress or are about to start very soon" in arthritis, inflammatory bowel disease, myocardial infarction, congestive heart failure and HIV replication in AIDS patients. Providing an update on Immunex' research with IL-1 receptor, Widmer noted that the compound is in trials or will go into trials for allergy, arthritis, graft versus host disease, EBD, HIV replication and acute myelogenous leukemia. IL-1 receptor has been tested in a Phase I trial of arthritis and in a Phase I/II trial of inhibition of allergic reactions to skin allergens, Widmer said. The compound most advanced in development at Cortech is the bradykinin antagonist Bradycor (CP-0127), a single action agent. Bradycor is in a double-blind, placebo-controbed, Phase II trial for sepsis. Cortech expects that a total of 500 patients will be enrolled in the study, which began in January. The patients all have hypotension, some signs of organ failure and systemic inflammatory response syndrome. The primary endpoint is 28-day mortality. Bradycor also is in a Phase II trial of 50 patients with bums with endpoints of edema, organ dysfunction and mortality; a Phase II trial in 20 patients with head injuries looking at edema and mortality; and a Phase II study of 50 patients with hantavirus with the endpoint of mortality. Whalley noted that "although we put Bradycor into clinical trials for sepsis, we felt it was worthwhile developing compounds that have dual activity." One of these compounds is CE-1037, a bradykinin-2 antagonist/neutrophil elastase inhibitor. Cortech plans to file an IND in early 1994 for a Phase I trial in adult respiratory distress syndrome. At the end of 1994, or in early 1995, the company plans to file INDs for cystic fibrosis and genetic emphysema. Two other dual-action compounds are CP-0364, a bradykinin-2 antagonist/bradykinin-1 antagonist heterodimer and CP-0494, a bradykinin-2 antagonist/opioid heterodimer. Both are in early research.
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