SmithKline Beecham plc, in collaboration with IDECPharmaceuticals Corp., has begun Phase III testing for IDEC-CE9.1,an anti-CD-4 primatized antibody being developed jointly withSmithKline for the treatment of rheumatoid arthritis.
The advent of Phase III testing also triggered a significant milestonepayment to IDEC from Middlesex, U.K.-based SmithKline under a1992 $60 million collaboration agreement. In March of this year,IDEC recognized $28.6 million in milestone payments. The amountof the current milestone payment was not disclosed. The 1992agreement calls for co-promotion rights in the U.S. and Canada.
IDEC-CE9.1 represents the first of a new class of monoclonalantibodies called primatized antibodies, Bill Rastetter, president andCEO of IDEC, told BioWorld Today. "Primatized means we havegenetically engineered those molecules from monkey and humanantibody components, rather than mice components," he explained.
IDEC has engineered these antibodies to be structurallyindistinguishable from human antibodies and less likely to elicitadverse reactions in humans. The antibody works by blocking a cell-surface receptor known as CD4 that appears on helper T cells andhelps mediate T-cell activation. Helper T cells normally play acentral roll in the immune response by directing the functions of otherimmune system cells.
In many autoimmune diseases, overactive T cells can drive theimmune system to attack and destroy healthy tissues. By binding toCD4, the IDEC-CE9.1 blocks the receptor's function, disables the Tcell and leads to down regulation of T-cell activity. This way, IDEC-CE9.1 may reduce excess T-cell activity and potentially slow thedisease process, without seriously affecting other immune systemfunctions.
In trials thus far, the company said, patients with active rheumatoidarthritis have experienced clinically significant improvements insigns and symptoms when treated intravenously with single ormultiple doses of IDEC-CE9.1.
In Phase II trials, a total of 122 patients received either 40 mg, 80 mgor 140 mg doses of IDEC-CE9.1 or placebo twice a day over a four-week period. All dose groups compared favorably to the rates of 42percent at the 40 mg dose, 47 percent at the 80 mg and 77 percent atthe 140 mg dose vs. 17 percent for the placebo group.
Responses were assessed using the ACR 20 guidelines, which requirean improvement in tender and swollen joint counts of at least 20percent along with improvement in three of five other disease-relatedparameters.
At the 140 mg dose level, three out of 16 patients experienced mildor moderate rashes. This rash, however, was not observed at lowermultiple doses or at much higher single doses.
Based on the Phase II experience, Phase III dosing has been slightlymodified. Patients in the current Phase III trial will receive eithertwice-weekly doses, weekly doses or placebo during the first monthof treatment. This induction regimen will be followed by periodicadministration of single doses of IDEC -CE9.1 with the goal ofmaintaining or extending disease remissions while reducing thefrequency of drug administration.
"The agent itself acts to regulate the patient's immune response, inthis case in the joints, which are being destroyed by the rheumatoidarthritis," Rastetter explained. "IDEC-CE9.1 is designed to interruptthat immune process early in the cascade of autoimmune events."
"It acts at the trigger point, the CD4 cell, and intervenes at that earlytrigger point before the cascade of autoimmune events can get out ofcontrol," he continued. "Others have taken the approach of trying tointervene late in the process. We believe that one of the difficulties ofdoing that is that you can intervene only at specific points, forexample sopping up TNF, and when the therapeutic agent is gone,the disease process can continue."
"When you intervene early in the disease process," Rastetter said, "atleast in theory, you can turn off the disease for weeks or months at atime. Early intervention in the cascade has the advantage of givingthe patient long drug holidays. By contrast, some of these otheragents have to be given twice a week."
IDEC, located in San Diego, was founded 10 years ago and wentpublic in 1991.
Another lead product for IDEC is IDEC-C2B8, designed fortreatment of non-Hodgkin's lymphoma. IDEC-C2B8 has completedPhase III testing and, Rastetter said, will be submitted for FDAapproval the first half of next year. n
-- Frances Bishopp
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