Immunex Corp.'s soluble tumor necrosis factor (TNF) receptorprovided no clinical benefit in a Phase II study of 141 patientswith sepsis, the company announced Monday.
Patients received either placebo, 0.15 mg/kg, 0.45 mg/kg or1.5 mg/kg TNF receptor. Immunex of Seattle reported thatpatients receiving the lowest doses of TNF receptor showed nodifference in mortality rate compared with those receivingplacebo, while patients treated at the higher doses had worseoutcomes than the placebo group.
The harmful effects seen in the high-dose group bring intoquestion the therapeutic strategy of inhibiting patients'inflammatory response to infection. It is believed thatcytokines, such as TNF and interleukin-1 (IL-1), play bothprotective and harmful roles during sepsis, so eliminating themcould have negative effects.
Immunex said it will not pursue additional sepsis trials withTNF receptor and is evaluating shifting additional resources tothe IL-1 study.
While several studies have shown TNF to be the centralmediator in sepsis, IL-2 is also a potent anti-inflammatorymediator, the company said. Both compounds entered clinicalsfor sepsis last year.
Immunex plans to continue development of TNF receptor forother indications. Steven Gillis, Immunex's acting chairman andchief executive officer, said that "while the results of this (TNFreceptor) study are not encouraging for pursuing additionalinvestigation of TNF receptor in sepsis, we believe the drug hastherapeutic potential in other disease settings."
Phase I studies are currently under way for treatment ofrheumatoid arthritis, HIV and Crohn's disease.
Immunex's stock (NASDAQ:IMNX) lost $1 a share to close at $17on Monday.
To date, sepsis drugs have had a bleak performance. Phase IIItrials of Centocor Inc.'s monoclonal antibody, Centoxin, XomaCorp.'s E5 monoclonal and Synergen Inc.'s Antril recombinantinterleukin-1 receptor did not show significant drug efficacy.All three companies are pursuing further Phase III studieswith their respective compounds.
With regard to TNF-related products, Centocor also foundunfavorable results with its humanized CenTNF chimericantibody. The company abandoned research for the sepsisindication last year following Phase I/II trial results, but iscontinuing clinical trials in patients with rheumatoid arthritisand inflammatory bowel disease.
Two other companies are pursuing TNF-related products. BayerAG is developing both a humanized and a murine monoclonalantibody to TNF. Bayer licensed the humanized antibody, inPhase II trials, from Celltech Group plc and the murineantibody, in Phase III in both the U.S. and Europe, from ChironCorp. And Genentech Inc. is in preclinicals with TNFR-IgG forsepsis.
Other approaches to sepsis treatment under developmentinclude Chiron's T88, an antibody to Gram-negative bacteriathat binds to a different antigen than Centoxin and E5. Chiron'sproduct is in a Phase III trial of approximately 850 patients.
Xoma and Incyte Pharmaceuticals are each developing abactericidal permeability-increasing protein. Xoma's rBPI-23, arecombinant derived fragment of natural human BPI, is inPhase I testing in healthy volunteers. The company is pursuingits 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-negativeendotoxin, is about to enter Phase II trials. For prophylactictreatment of sepsis, the compound tolerizes the immunesystem so that key cells respond to inflammation but not somuch as to cause shock and death. A slightly differentformulation of MPL is in Phase II to prevent or reduce thedamage of cardiac ischemia reperfusion injury.
Additional compounds in development for sepsis includeCortech Inc.'s bradykinin antagonist Bradycor, in Phase IItrials; Scios Nova's neutrophil inhibitor NPC 15669 andbradykinin antagonist NPC 17761; ImClone Systems Inc.'s IL-1inhibitor Septanil, under development with Miles Laboratories;and Vertex Pharmaceuticals Inc.'s interleukin-1 convertingenzyme (ICE).
-- Brenda Sandburg News Editor
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