Background In a Phase 2b double-blind, placebo-controlled randomized clinical trial, 222 subjects with seropositive, active rheumatoid arthritis received infusions of 800mg of TRU-015, a mono-specific ADAPTIR™ (modular protein technology) drug candidate directed against CD20+ B cells, or placebo. To prevent adverse drug reactions, all subjects randomized to active TRU-015 concomitantly received active systemic steroids. Randomization to 3 treatment groups occurred at Baseline (BL). The study consisted of 2 parts, Part A started at Baseline until Week 24, and Part B from Week 24 to Week 52. Here we present the results from Part A.
Objectives To evaluate the clinical activity, safety, pharmacodynamics (PD), and pharmacokinetics (PK) profiles of TRU-015 800 mg IV throughout 24 weeks after single or dual doses.
Methods Eligible subjects (ARA 1987 criteria, ACR class I-III) were randomized to one of 3 groups: Single Dose TRU-015 800 mg IV at Baseline only (SD); Induction dose regimen, TRU-015 800 mg IV at Baseline and Week 12 (ID); Placebo at Baseline and Week 12. All subjects continued on background methotrexate. All subjects who received any portion of test article were included in modified intent to treat population for efficacy and safety evaluation. Efficacy assessments included ACR20/50/70 (mITT) and the individual components, and quality of life questionnaires. PK parameters were calculated from serum concentration data analyzed by validated ELISA. PD was evaluated using CD19+ B cell counts.
Results At Week 24, ACR20 responders were significantly higher in TRU-SD (61.3%) and TRU-ID (67.1%) arms than in the placebo (43.2%) arm (p<0.030 and p<0.005, respectively, compared to placebo). ACR70 response rates at Week 24 were also higher in TRU-SD (9.3%) and TRU-ID (9.6%) arms than in the placebo (2.7%) arm (p=0.089 and p=0.079, respectively compared to placebo). Although Week 24 ACR50 response rates (primary endpoint) were higher in both TRU-SD (29.3%) and TRU-ID (27.4%) treatment arms than placebo (16.2%), statistical significance (p>0.05) was not reached. Infusion reactions (rash and urticaria) were observed in 18.9% of subjects and were more frequent in the TRU-SD (24%) and TRU-ID (27.4%) treatment arms compared with the Placebo arm (5.4%). The incidence of other AE and SAE did not differ among treatment groups. Pharmacodynamics: Median CD19+ B cells counts two weeks following TRU-015 administration were reduced by over 100-fold and this reduction persisted in the TRU-ID cohort through 24 weeks.
Conclusions TRU-015 treatment was well-tolerated and resulted in a higher proportion of subjects achieving ACR 20, ACR50 and ACR70 as compared to placebo. However, the clinical improvement observed with the primary endpoint (ACR50) was not sufficient to yield a significant outcome. CD19+ B cell depletion was rapid and persisted throughout the study. Transient infusion reactions were more frequent in both treatment arms compared with the placebo arm. All other AEs and SAEs did not differ among treatment arms.
Disclosure of Interest: A. Brodsky Grant/research support from: Pfizer Inc, E. Diri Grant/research support from: Pfizer Inc; La Roche, UBC, I. Garcia-DeLaTorre Grant/research support from: Pfizer Inc, Sanofi, Bristol Myers, D. Alvarez Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Bencan Consultant for: Pfizer Inc, J. Bukowski Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, C. Zang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc
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