Immunex Corp.'s soluble tumor necrosis factor (TNF) receptor provided no clinical benefit in a Phase II study of 141 patients with sepsis, the company announced Monday.
Patients received either placebo, 0.15 mg/kg, 0.45 mg/kg or 1.5 mg/kg TNF receptor. Immunex of Seattle reported that patients receiving the lowest doses of TNF receptor showed no difference in mortality rate compared with those receiving placebo, while patients treated at the higher doses had worse outcomes than the placebo group.
The harmful effects seen in the high-dose group bring into question the therapeutic strategy of inhibiting patients' inflammatory response to infection. It is believed that cytokines, such as TNF and interleukin-1 (IL-1), play both protective and harmful roles during sepsis, so eliminating them could have negative effects.
Immunex said it will not pursue additional sepsis trials with TNF receptor and is evaluating shifting additional resources to the IL-1 study.
While several studies have shown TNF to be the central mediator in sepsis, IL-2 is also a potent anti-inflammatory mediator, the company said. Both compounds entered clinicals for sepsis last year.
Immunex plans to continue development of TNF receptor for other indications. Steven Gillis, Immunex's acting chairman and chief executive officer, said that "while the results of this (TNF receptor) study are not encouraging for pursuing additional investigation of TNF receptor in sepsis, we believe the drug has therapeutic potential in other disease settings."
Phase I studies are currently under way for treatment of rheumatoid arthritis, HIV and Crohn's disease.
Immunex's stock (NASDAQ:IMNX) lost $1 a share to close at $17 on Monday.
To date, sepsis drugs have had a bleak performance. Phase III trials of Centocor Inc.'s monoclonal antibody, Centoxin, Xoma Corp.'s E5 monoclonal and Synergen Inc.'s Antril recombinant interleukin-1 receptor did not show significant drug efficacy. All three companies are pursuing further Phase III studies with their respective compounds.
With regard to TNF-related products, Centocor also found unfavorable results with its humanized CenTNF chimeric antibody. The company abandoned research for the sepsis indication last year following Phase I/II trial results, but is continuing clinical trials in patients with rheumatoid arthritis and inflammatory bowel disease.
Two other companies are pursuing TNF-related products. Bayer AG is developing both a humanized and a murine monoclonal antibody to TNF. Bayer licensed the humanized antibody, in Phase II trials, from Celltech Group plc and the murine antibody, in Phase III in both the U.S. and Europe, from Chiron Corp. And Genentech Inc. is in preclinicals with TNFR-IgG for sepsis.
Other approaches to sepsis treatment under development include Chiron's T88, an antibody to Gram-negative bacteria that binds to a different antigen than Centoxin and E5. Chiron's product is in a Phase III trial of approximately 850 patients.
Xoma and Incyte Pharmaceuticals are each developing a bactericidal permeability-increasing protein. Xoma's rBPI-23, a recombinant derived fragment of natural human BPI, is in Phase I testing in healthy volunteers. The company is pursuing its development for sepsis and other infections. Incyte's BPI, being developed with Genentech, is in advanced preclinicals.
Ribi ImmunoChem Research Inc.'s monophosphoryl lipid A (MPL) immunomodulator, a derivative of Gram-negative endotoxin, is about to enter Phase II trials. For prophylactic treatment of sepsis, the compound tolerizes the immune system so that key cells respond to inflammation but not so much as to cause shock and death. A slightly different formulation of MPL is in Phase II to prevent or reduce the damage of cardiac ischemia reperfusion injury.
Additional compounds in development for sepsis include Cortech Inc.'s bradykinin antagonist Bradycor, in Phase II trials; Scios Nova's neutrophil inhibitor NPC 15669 and bradykinin antagonist NPC 17761; ImClone Systems Inc.'s IL-1 inhibitor Septanil, under development with Miles Laboratories; and Vertex Pharmaceuticals Inc.'s interleukin-1 converting enzyme (ICE).
-- Brenda Sandburg News Editor
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