WASHINGTON _ After striking out as a treatment for sepsis,antibodies aimed at inhibiting tumor necrosis factor (TNF) havefinally gotten on base in early-stage studies of rheumatoid arthritispatients.Two anti-TNF antibodies, one developed by Centocor Inc., ofMalvern, Pa., and the other developed by Celltech Ltd., of Slough,England, demonstrated efficacy in two separate double-blinded,placebo-controlled, randomized Phase II trials. The findings, if theyare reproduced in further studies, could lead to a breakthrough forrheumatoid arthritis patients.Rheumatoid arthritis is a chronic disease that causes pain, swellingand destruction of the joints and leads to severe disability in manycases. It affects about 2.5 million people worldwide and strikesmost victims between the ages of 20 and 45.Results from Centocor's work with its chimeric anti-TNF antibody,CenTNF (cA2) were published in today's issue of The Lancet. Datafrom Celltech's trial of a humanized anti-TNF antibody known asCDP571 will be presented at the American College ofRheumatology's annual meeting Oct. 23-27 in Minneapolis.Centocor also will present data at next week's meeting.If successful against rheumatoid arthritis , anti-TNF antibodiescould at last vindicate the therapeutic approach of inhibitingcytokines. Cytokines are messenger proteins _ such as TNF,interleukin-1 (IL-1) and interleukin-6 (IL-6) _ produced by whiteblood cells that act to signal various cells in the body and mediatethe immune system and its inflammatory responses.Researchers believed that by inhibiting cytokines they could treatsepsis, a clinical syndrome in which the immune system overreactsto infection. However, numerous anti-cytokine drugs have failed insepsis trials. While cytokines can cause harm, as they do in sepsisand in rheumatoid arthritis , they are also central components of thehuman immune system that have evolved over millions of years andplay a critical, if not fully understood, role.Brian Butcher of the Arthritis Foundation told BioWorld thatmodifying the biological response in a targeted fashion, such asinhibiting TNF or IL-1, would be better than the "shotgun blast"delivered by current therapies for patients with severe rheumatoidarthritis, such as methotrexate and gold therapy which are highlytoxic.In a clinical trial conducted at four centers in England andpublished in Lancet, rheumatoid arthritis patients who receivedCenTNF showed a highly statistically significant dose-relatedresponse. In the study, 73 patients were randomized to three groups(placebo, 1 mg/kg CenTNF or 10 mg/kg CenTNF). The primaryendpoint was achievement of a lowered disease score at four weeks.In the placebo group, two out of 24 (8 percent response rate)patients improved at four weeks. In the group that received a lowdose of CenTNF, 11 out of 25 (44 percent) patients improved. Andin the group that received a single dose of 10 mg/kg of CenTNF, 19out of 24 (79 percent) improved. According to Centocor's chiefscientific officer, James Woody, unpublished data show thatpositive responses to CenTNF endured for up to four months insome patients."It's remarkable that a single dose would last that long," he said."This is the first drug that's ever done that in rheumatoid arthritis.We achieved not just a remission but a clinical benefit, as well. Thisis a breakthrough."Few side effects were noted, but one patient in the CenTNF studydid develop pneumonia which was "probably" drug-related.Hambrecht & Quist analyst Alex Zisson told BioWorld that whileCentocor's Phase II results were encouraging, "Everyone on WallStreet now hopefully understands that there's a long way between aPhase II trial and a successful FDA review and product launch."Zisson added that while the drug clearly showed activity againstdisease and safety, the question of how it compares to currentstandard therapy is left unanswered by this trial.According to an abstract published by the American College ofRheumatology, the effects of CDP571 on rheumatoid arthritispatients were seen within one week of administration. At the 10mg/kg dose, there were reductions in measurements of pain,tenderness and swelling. In addition, the drug was reportedly welltolerated. n

-- Lisa Piercey Washington Editor

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