As a progressive, debilitating, inflammatory disease, rheumatoidarthritis presents tremendous challenges to physicians and researcherstrying to stymie the runaway immune reactions that destroy joints.Clinical results presented at the American College of Rheumatologymeeting this week offer more hope that biologic response modifiersmay one day offer significant relief with few side effects to a numberof rheumatoid arthritis (RA) patients.

Highlights of news from the conference include:

Mopping Up TNF

Tumor necrosis factor (TNF) is a cytokine which is secreted bymacrophages during an immune attack. TNF travels throughout thebloodstream turning on inflammation. By binding to TNF receptorson the surface of cells, TNF can activate other immune cells.Immunex Corp., of Seattle, has developed a protein that fuses theactive part of the TNF receptor molecule to a humanimmunoglobulin. By injecting this fusion protein, the researchershope to "mop up" excess TNF in the bloodstreams of RA patientsand slow the immune reaction, said Immunex's medical director ofclinical development Consuelo Blosch. "Basically we are trying touse a natural product to combat the disease."

In a multicenter Phase II clinical trial of 180 people with active RA,researchers administered the TNF(p80) receptor fusion protein ineither 0.25 mg/m2, 2 mg/m2, or 16 mg/m2 doses or administered aplacebo twice a week for three months. At the end of the study 75percent of the patients on the largest dose had significantimprovement of the RA symptoms compared to 14 percent of theplacebo group. The only side effects noted were redness at theinjection site and some upper respiratory infections. The researcherssaw no allergic reactions to the drug.

"The drug was extremely well-tolerated and the responses we sawwere highly significant," Blosch told BioWorld Today.

Thwarting Interleukin-1

Amgen Inc., of Thousand Oaks, Calif., is taking aim at an entirelydifferent cytokine involved in the inflammatory response. Interleukin-1 (IL-1) is released by cells at the site of inflammation.

In RA, the cytokine perpetuates the disease by activating cells liningthe blood vessels to cause inflammation and destroying bone andcartilage in the joints. Curiously, a protein produced by the bodycalled IL-1ra can stymie IL-1's inflammatory activity. Amgengenetically engineered this anti-inflammatory protein as a drug to testin patients.

In a European Phase II clinical trial of IL-1ra, patients receivedeither a placebo or a 30 mg, 75 mg or 150 mg dose of the drug as asubcutaneous injection every day for three months. Forty-threepercent of patients on the highest dose of IL-1ra had significantimprovement of their symptoms compared to 27 percent of theplacebo patients. The most common side effect was redness at theinjection site.

Amgen currently is deciding whether or not to take the drug intoPhase III clinical trials.

Stopping Cells That Make Inflammation

T cells take center stage in the inflammatory process directing theinflammatory activities of other immune cells. IDECPharmaceuticals, of La Jolla, Calif., and SmithKline Beecham, ofCollegeville, Pa., have chosen to attack RA by creating an antibodythat stops T cells from participating in the immune response.

All T cells have a CD4 receptor on their cell surface; presumably,blocking the T cell with an anti-CD4 antibody could disable the Tcell and dampen inflammation. However, such antibodies could causeallergic reactions, so IDEC genetically engineered the antibodies tocontain primate sequences in order to combat such reactions.

Results of a three-month Phase II clinical trial testing twice-weeklydoses of 140 mg, 80 mg and 40 mg infusions of the antibody againstplacebo show that 47 percent of the patients on the 80 mg dose and42 percent of the patients on the 40 mg dose had significantimprovement of their RA symptoms compared to 17 percent of thepatients on placebo. The 140 mg group had to be stopped as theresult of rashes.

"SmithKline Beecham and we at IDEC are making plans with theFDA to put the antibody into Phase III trials," said Nabil Hannasenior vice president for research and development at IDEC. "Wehope to start accrual by the end of this year." n

-- Lisa Seachrist Washington Editor

(c) 1997 American Health Consultants. All rights reserved.

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