Volume 9 Supplement 3

6th Global Arthritis Research Network (GARN) Meeting

Open Access

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

  • DJ Burge1,
  • C Shu2,
  • RW Martin3,
  • TW Littlejohn4,
  • DJ Wallace5,
  • J Taborn6,
  • WR Palmer7 and
  • A Kivitz8
Arthritis Research & Therapy20079(Suppl 3):P32

https://doi.org/10.1186/ar2258

Published: 19 October 2007

Background

Protein therapeutics directed toward CD20 antigen on B lymphocytes have been demonstrated to be highly effective in the treatment of rheumatoid arthritis (RA) [13]. 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.

Authors’ Affiliations

(1)
Trubion Pharmaceuticals
(2)
Wyeth
(3)
Arthritis Education & Treatment Center
(4)
Piedmont Medical Research Association
(5)
Wallace Rheumatic Study Center
(6)
Midwest Arthritis Center
(7)
Westroads Medical Group
(8)
Altoona Center for Clinical Research

References

  1. 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
  2. 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
  3. 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
  4. 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
  5. 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
  6. 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

Copyright

© BioMed Central Ltd 2007