TRU-015, a small modular immunopharmaceutical (SMIP™) drug candidate directed against CD20, demonstrates clinical improvement in subjects with rheumatoid arthritis

Background

Protein therapeutics directed toward CD20 antigen on B lymphocytes have been demonstrated to be highly effective in the treatment of rheumatoid arthritis (RA) [1–3]. Small modular immunopharmaceutical drugs are single-chain polypeptides that are smaller than antibodies. TRU-015 is a CD20-directed small modular immunopharmaceutical drug candidate that effectively depletes B lymphocytes in cynomolgus monkeys in a dose-dependent manner, and improves survival in mouse xenograft tumor models [4, 5].

Objective

Previously, a dose-escalation study in subjects with RA demonstrated that TRU-015 was generally well tolerated and resulted in dose-dependent B-lymphocyte depletion [6]. The present study was designed to further assess the safety and pharmacokinetics of TRU-015 and to additionally evaluate clinical responses in RA subjects with active disease treated with TRU-015.

Methods

Thirty-six RA subjects with active disease despite background methotrexate were enrolled in this randomized, double-blind, multicenter, placebo-controlled study. Subjects were enrolled into one of three cohorts in a 10:2 (active:placebo) ratio to receive TRU-015 as a single intravenous infusion of 5 mg/kg, two infusions of 2.5 mg/kg, or two infusions of 7.5 mg/kg. Subjects in cohorts with two infusions received the infusions 1 week apart. Subjects were premedicated with steroids, but only peri-infusional doses were used.

Results

Interim data are available in this ongoing study. TRU-015 was generally well tolerated. No significant infusion reactions were observed. No infectious or noninfectious serious adverse events related to TRU-015 have been reported. B-cell depletion was demonstrated in all cohorts. The exposure of TRU-015 following two intravenous infusion of 2.5 mg/kg was comparable with that following a single infusion of 5 mg/kg. ACR20 responses have been observed in 72% of all evaluable subjects and 82% of rheumatoid factor-positive subjects. At 12 weeks, response rates were similar in each of the cohorts. Longer-term observation is ongoing.

Conclusion

TRU-015, administered at doses resulting in B-cell depletion, is generally well tolerated. No significant safety issues have been observed. This study provides evidence that therapy with TRU-015 results in meaningful clinical benefit in subjects with active RA despite methotrexate therapy. Further exploration is required to determine the optimal dose of TRU-015.