Volume 9 Supplement 3
TRU-015, a small modular immunopharmaceutical (SMIP™) drug candidate directed against CD20, demonstrates clinical improvement in subjects with rheumatoid arthritis
© BioMed Central Ltd 2007
Published: 19 October 2007
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].
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 . 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.
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.
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.
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.
- Edwards J, Szczepanski L, Szechinski J, et al: Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004, 350: 2572-2581. 10.1056/NEJMoa032534.View ArticlePubMedGoogle Scholar
- Emery P, Fleischmann R, Filipowicz-Sosnowska A, for DANCER Study Group, et al: The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIb randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 2006, 54: 1390-1400. 10.1002/art.21778.View ArticlePubMedGoogle Scholar
- Cohen SB, Emery P, Greenwald MW, for the Reflex Trial Group, et al: Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase II trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006, 54: 2793-2806. 10.1002/art.22025.View ArticlePubMedGoogle Scholar
- Barone D, Baum P, Ledbetter J, Ledbetter MH, Mohler K: Prolonged depletion of circulating B-cells in cynomolgus monkeys after a single dose of TRU-015, A novel CD20 directed therapeutic. Ann Rheum Dis. 2005, 64: 159-10.1136/ard.2003.020297.View ArticleGoogle Scholar
- Barone D, Nilsson C, Ledbetter J, Hayden-Ledbetter M, Mohler K: TRU-015, a novel CD20-directed biologic therapy, demonstrates significant anti-tumor activity in human tumor xenograft models. J Clin Oncol ASCO Annual Meeting Proc. 2005, 23 (Suppl): 2549-Google Scholar
- Burge DJ, Bookbinder SA, Kivitz AJ, et al: Phase 1 study of TRU-015, a CD20 directed small modular immunopharmaceutical (SMIP) protein therapeutic in subjects with rheumatoid arthritis. Ann Rheum Dis. 2006, 65 (Suppl II): 180-Google Scholar