Repeat-cycle study of high-dose intravenous 4162W94 anti- @entity404 humanized monoclonal antibody in XXXX . A randomized placebo-controlled trial.

@entity1 @entity404 @entity1910 @entity1333 @entity2905 @entity309
OBJECTIVE: Results of an earlier open-label pilot study showed that 4162W94 was a relatively non-depleting anti- @entity404 monoclonal antibody that induced >80% down-modulation of @entity404 molecules from the surface of T lymphocytes. This placebo-controlled repeat-cycle study was conducted in active @entity309 ( @entity309 ) @entity1 to determine the duration of @entity404 blockade required to achieve lasting clinical benefit. METHODS: Following DMARD washout, 48 @entity1 (i.e. three cohorts of 16 @entity1 ) with ACR-defined @entity309 were to be dosed with 1 (cohort 1), 2 (cohort 2) or 3 (cohort 3) cycles of 5x300 mg 4162W94 or placebo (12 and 4 @entity1 per cohort respectively) at monthly intervals. There was at least 3 months of follow-up after dosing. Clinical outcome was assessed in evaluable @entity1 (receiving at least 80% of each dose course) using ACR20 criteria (required on two consecutive visits). @entity404 lymphocyte counts and adverse events were also monitored. RESULTS: Sixteen @entity1 were dosed in each of the first two cohorts; however, the dose was reduced in cohort 3 after five @entity1 had received up to two dose cycles due to accumulating evidence of a high frequency of @entity1910 . These @entity1 were analysed according to the number of cycles received. A further eight @entity1 received 5x100 mg for one to three cycles prior to stopping the study for administrative reasons. Four of 13 (P=0.119 vs placebo) and 7/13 (P=0.015 vs placebo) in cohorts 1 and 2 respectively achieved ACR20 response on at least two consecutive occasions. No @entity1 receiving 5x100 mg/day or placebo achieved ACR20. Four @entity1 were still responding at the end of the 3-month follow-up period. @entity404 lymphocyte suppression (<0.2x10(9)/l on at least two successive occasions) occurred in 11/34 @entity1 who received 4162W94 vs none on placebo. @entity1910 occurred in 21/34 monoclonal antibody-treated @entity1 , including one case of biopsy-confirmed @entity1333 and 1/11 placebo @entity1 . CONCLUSION: 4162W94 demonstrated significant clinical efficacy in this study. However, because of unacceptable @entity404 @entity2905 and @entity1910 , the original hypothesis that prolonged @entity404 blockade would give lasting clinical benefit was not tested.
