Phase 1 study of TRU-015, a CD20-directed small modular immunopharmaceutical (SMIP™) protein therapeutic, in subjects with rheumatoid arthritis

Background

CD20-directed therapy is well established in oncology, and was recently demonstrated to be highly effective in the treatment of rheumatoid arthritis (RA) [1]. Small modular immunopharmaceutical drugs are smaller than antibodies yet are capable of utilizing effector functions of antibody-dependent cellular cytotoxicity, complement-mediated cytotoxicity and apoptotic signaling. TRU-015 is a small modular immunopharmaceutical drug candidate that is specific for CD20. TRU-015 has been demonstrated to effectively deplete B lymphocytes in cynomolgus monkeys in a dose-dependent manner, and to improve survival in mouse xenograft tumor models [2, 3].

Objectives

This phase 1 dose escalation study was performed to evaluate the safety, pharmacokinetics and pharmacodynamics of TRU-015 in subjects with RA.

Methods

Thirty-seven RA subjects receiving a stable background of methotrexate were enrolled in eight dosage groups (single dosages of TRU-015 of 0.015, 0.05, 0.15, 0.5, 1.5, 5, or 15 mg/kg, or two doses of 15 mg/kg given 1 week apart (30 mg/kg)). Safety was assessed at baseline, during infusion and at prespecified intervals after infusion by clinical (adverse events, physical examination, vital signs) and laboratory parameters. Serum samples were collected for pharmacokinetic analysis. Pharmacodynamic response was measured using B-cell counts (CD19⁺ cells by flow cytometry) at prespecified timepoints. Subjects were evaluated for a minimum of 4 weeks and until B-cell recovery.

Results

At least four subjects were exposed at each dose level. TRU-015 was generally well tolerated. No dose-limiting toxicities were observed, and no serious adverse events have been reported. Decreases in peripheral B-cell counts were observed in all dose groups at the first time-point after drug administration (24 hours), with doses ≥0.5 mg/kg causing depletion of peripheral B cells. The degree, duration, and recovery of B-cell depletion were dose dependent. Pharmacokinetic parameters of TRU-015 were calculated for cohorts receiving 0.5 mg/kg and higher, and are presented in Table 1. The overall mean half-life of TRU-015 was 295 hours.

Table 1 Pharmacokinetics of TRU-015

Conclusion

TRU-015, a novel CD20-directed therapy, was generally well tolerated and resulted in dose-dependent B-lymphocyte depletion. Following intravenous infusion, pharmacokinetic properties of TRU-015 (area under the curve, maximum concentration of drug) were approximately dose proportional. Further evaluation of TRU-015 is warranted for the treatment of RA, and other autoimmune diseases.