A drug that lost its fight against sepsis last year has wonout against rheumatoid arthritis. (See BioWorld Today,March 9, 1994, p. 1.)
A Phase II trial of tumor necrosis factor receptor (TNFr)gave high marks to its highest-dose cohort in reducing thenumber of swollen or painful arthritic joints, whileimproving sedimentation rates and C-reactive protein.
Rheumatologist Larry Moreland, who directs theUniversity of Alabama's Arthritis Clinical InterventionProgram, reported these TNFr results Nov. 15, 1995, inBoston to the second annual conference on InflammatoryCytokine Antagonists. He had previously conducted thePhase I study of TNFr as a potential rheumatoid arthritistherapeutic.
"It wasn't until about a week before this meeting,"Moreland told BioWorld Today, "that the Phase II resultsbecame available."
The blinded, placebo-controlled Phase II trial, hereported, randomized its 180 patients with advancedrheumatoid arthritis to three 45-person dose-escalatingcohorts plus a placebo contingent. They receivedsubcutaneous injections twice weekly for 85 days _three months. The high-dose recipients experienced a 64-percent reduction in painful joints, and 58 percent fewerswollen joints.
Sedimentation rate, a laboratory marker of diseaseintensity, decreased 31 percent in high-dose recipients,while rising 21 percent in placebo patients.
Local erythema at the injection site was the only sideeffect, Moreland observed, "but this did not requirepatients stopping the drug at all."
Immunex Corp., of Seattle, which created TNFr,sponsored the multicenter trial, and is now lookingtoward a follow-on pivotal Phase III study.
"We're developing our Phase III strategy right now," saidthe company's senior vice president for pharmaceuticaldevelopment, Peggy Phillips. As TNF-blockers forrheumatoid arthritis "is quite a competitive field," shetold BioWorld Today, "we hope to launch our Phase IIIwithin the first half of next year."
As Phillips describes the ravages of TNF, a rationale forblocking this cytokine's inflammatory chain reaction inthe joint disease is clear: "TNF-alpha attacks connectivetissue, and evokes production of collagenase," sheexplained. "This is responsible for disruptingextracellular collagen matrix in inflamed tissue.
"Transgenic mice carrying the TNF-alpha gene developchronic inflammatory rheumatoid arthritis," Phillipsadded.
All of which leads to Immunex's strategy: Sopping upTNF with an influx of its own receptor molecule. This isa recombinant version of the natural cytokine's receptor,which binds to two molecules of TNF, and thus blocks itsability to promote inflammation.
"There are two TNF receptors," Phillips pointed out,"P60 and P80. We are developing P80. Hoffmann-LaRoche Inc., of Nutley, N.J., is developing P60."
An alternative diversionary movement relies onmonoclonal antibodies to scavenge TNF molecules.Celltech Ltd., in Slough, U.K., and Centocor Inc., ofMalvern, Pa., both are pursuing this approach.
"All four companies," Phillips said, "are close to PhaseIII strategies."
Commenting on the "statistically significant" Phase IIdata presented in Boston, the Atlanta-based ArthritisFoundation welcomed its "encouraging yet verypreliminary results that must be confirmed in largerstudies to determine its true effectiveness and theduration of improvement."
But beyond this next step, the Foundation's group vicepresident for research, Brian Butcher, added anotherproviso: "If ultimately proven beneficial, the treatmentalso must overcome limits to its practicality due to theneed for multiple injections."
Moreland echoes this marketability stricture: "If you canget a small peptide in there, or something else that will beorally active, you're going to be way far ahead."
That pharmaceutical truism is not lost on Immunex, or itscompetitors.
"Our ideal," said Phillips, "is an orally delivered drug.One strategy we're looking at as a second-generationalternative to TNFr is a recently cloned tumor necrosisfactor protease from which a small-molecule inhibitorcould be derived."
Farther out on the curve, she added, "Another mechanismfor delivering cytokine receptors may be by inhalation ofdry powder." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.