Trubion Pharmaceuticals Inc (SEATTLE, Washington), a biopharmaceutical company creating a pipeline of product candidates to treat autoimmune disease and cancer, announced that TRU-015, its lead Small Modular ImmunoPharmaceutical (SMIPâ„¢) drug candidate for the treatment of rheumatoid arthritis (RA), provided statistically significant efficacy after a single infusion of 800 mg or 1600 mg compared with placebo for a 24-week period. In addition, repeat administration with the agent was well tolerated and resulted in a consistent pharmacokinetic (PK) and pharmacodynamic (PD) profile. TRU-015 is a novel single-chain polypeptide targeting CD20 (B-cell depleting) and is engineered for potent ADCC (antibody dependent cellular cytotoxicity) activity and attenuated CDC (complement dependent cytotoxicity) activity. Trubion Pharmaceuticals Inc is codeveloping TRU-015 for RA with Wyeth Pharmaceuticals.

The randomized, double-blind, placebo-controlled, multicenter clinical trial included 276 patients randomized equally into five groups that received a single intravenous infusion of TRU-015 200 mg, 400 mg, 800 mg, 1600 mg, or placebo. Improvement in DAS28 compared with placebo was statistically significant in the 800-mg dose group at 12 weeks and in the 1600-mg dose group at 16 weeks, and at all subsequent assessments. At 24 weeks, ACR-20, -50, and -70 response rates in the 1600-mg dose group were 61%, 13%, and 4%, respectively; in the 800-mg dose group, the rates were 65%, 26%, and 0%, respectively; and in the placebo group, they were 33%, 9%, and 2%, respectively.

At 24 weeks, significant improvement in the Health Assessment Questionnaire Disability Index (HAQ-DI) was observed in the TRU-015 1600-mg group (-0.70 vs -0.37, P = .008) and the 800- group (-0.64 vs -0.37, P = .035). Median C-reactive protein (CRP) improvement was 57% in the 1600-mg group, 48% in the 800-mg group, and 28% in the placebo group. TRU-015 was generally well tolerated and only one subject in the 400-mg group experienced a grade 3 adverse event (AE) on day of infusion.

The objective of the re-treatment study was to evaluate the safety, PD, PK, and immunogenicity of TRU-015 for RA with repeated doses after receiving initial administration in a phase I/IIa study. Fifty-four patients were eligible for re-treatment with a single course of 5 mg/kg or higher in a previously conducted TRU-015 phase I/IIa study and, at the time of the analysis, re-treatment data were available for 36 patients. PD response of B-cells was also evaluated after initial treatment and after re-treatment.

B-cell depletion and recovery following re-treatment with the agent was comparable to that seen after initial treatment. Ongoing patient evaluations showed maintenance of ACR responses with repeated single doses of TRU-015 at 6-month intervals through at least two re-treatment courses. Total serum IgG levels remained within normal limits. In addition, subjects treated with three or more courses of therapy showed persistent decreases in RF and IgM levels without experiencing decreases in IgG or IgA levels. No neutralizing antibodies to the agent had been detected at the time of the assessment; the drug was generally well tolerated and no grade 3 or 4 AEs occurred on day of infusion.

Trubion and Wyeth have agreed on the design of the next clinical trial, and both companies are working to finalize protocol details and plans for study initiation. The randomized, double-blind, placebo-controlled, multicenter trial will examine ways to further optimize efficacy while evaluating dosing schedule. In addition to the ongoing development of TRU-015 for RA, an IND has been filed for the agent in systemic lupus erythematosus. Approximately one third to one half the size of conventional therapeutic monoclonal antibodies, SMIP drugs are engineered to possess the full binding and activity function of a monoclonal antibody and exhibit selective target binding and long in vivo half-lives.