Advertisement
Clinical Therapeutics
Advanced searchSave search
Research Article| Volume 30, ISSUE 10, P1806-1816, October 2008

Download started.

Ok

Pharmacokinetic and pharmacodynamic properties of TRU-015, a CD20-directed small modular immunopharmaceutical protein therapeutic, in patients with rheumatoid arthritis: A phase I, open-label, dose-escalation clinical study

DOI:https://doi.org/10.1016/j.clinthera.2008.10.017
Pharmacokinetic and pharmacodynamic properties of TRU-015, a CD20-directed small modular immunopharmaceutical protein therapeutic, in patients with rheumatoid arthritis: A phase I, open-label, dose-escalation clinical study
Previous ArticlePharmacokinetic properties and tolerability of bevirimat and atazanavir in healthy volunteers: An open-label, parallel-group study
Next ArticlePharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: A dose—block-randomized, double-blind, placebo-controlled, ascending single-dose, phase I study
      This paper is only available as a PDF. To read, Please Download here.

      Abstract

      Background: TRU-015 is a small modular immunopharmaceutical protein drug that binds to CD20 and effectively depleted B cells in nonhuman primates.
      Objective: The aim of this clinical study was to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties, immunogenicity, and tolerability of TRU-015 in patients with rheumatoid arthritis (RA).
      Methods: This Phase I, open-label, dose-escalation clinical study was conducted at 4 medical centers in the United States. Patients with RA who were receiving stable-dose methotrexate were enrolled in 1 of 8 dose groups and received TRU-015 as a single IV dose of 0.015, 0.05, 0.15, 0.5, 1.5, 5, or 15, or 2 IV doses of 15 mg/kg, administered 7 days apart (30 mg/kg). Patients were enrolled in the next higher dose cohort based on the tolerability observed in the prior cohort. Prior to TRU-015 infusion, patients were premedicated with an antihistamine and acetaminophen and may have received a corticosteroid at the investigator's discretion. Serum samples were collected for analysis of PK properties (serum t½) and neutralizing antibodies to TRU-015; enzyme-linked immunosorbent assays and a cell-based neutralizing assay were used to evaluate samples from patients. PD response was measured using B-cell (CD19+-cell) count using flow cytometry at prespecified time points. Tolerability was assessed during drug infusion and at prespecified time points after infusion using physical examination and laboratory analysis. Patients were followed for ≥4 weeks and until B-cell recovery.
      Results: Thirty-seven patients were enrolled. Most were female (81%) and white (95%); the mean age was 53 years. Serum t½ ranged from 12 to 19 days. B-cell depletion generally increased in degree and duration with increasing doses. No neutralizing antibodies to TRU-015 were detected. Mild adverse events (AEs) included back pain, headache, peripheral edema, and upper respiratory infection (5 patients each). Mild urticaria occurred in 1 patient. Grade 3 AEs included hypertension, arthralgia, and urticaria and bronchospasm (1 patient each). No dose-limiting toxicity was found.
      Conclusions: In this small population of patients with RA, the Cmax and the AUC appeared to increase in a dose-proportional manner. The mean t½ ranged from 12 to 19 days. TRU-015 was associated with dose-dependent B-cell depletion and an acceptable tolerability profile.

      Key words:

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Clinical Therapeutics
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Register: Create an account
      Institutional Access: Sign in to ScienceDirect

      References

        • Scott DL
        • Smith C
        • Kingsley G
        Joint damage and disability in rheumatoid arthritis: An updated systematic review.
        Clin Exp Rheumatol. 2003; 21: S20-S27
        • Doran MF
        • Pond GR
        • Crowson CS
        • et al.
        Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period.
        Arthritis Rheum. 2002; 46: 625-631
        • Hazes JM
        • Silman AJ
        Review of UK data on the rheumatic diseases-2. Rheumatoid arthritis.
        Br J Rheumatol. 1990; 29: 310-312
        • Corbett M
        • Dalton S
        • Young A
        • et al.
        Factors predicting death, survival and functional outcome in a prospective study of early rheumatoid disease over fifteen years.
        Br J Rheumatol. 1993; 32: 717-723
        • The American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines
        Guidelines for the management of rheumatoid arthritis: 2002 Update.
        Arthritis Rheum. 2002; 46: 328-346
        • Furst DE
        • Breedveld FC
        • Kalden JR
        • et al.
        Updated consensus statement on biological agents, specifically tumour necrosis factor (alpha) (TNF[alpha]) blocking agents and interleukin-1 receptor antagonist (IL-1ra), for the treatment of rheumatic diseases, 2005.
        Ann Rheum Dis. 2005; 64: iv2-iv14
        • Choy EH
        • Smith C
        • Doré CJ
        • Scott DL
        A meta-analysis of the efficacy and toxicity of combining disease-modifying anti-rheumatic drugs in rheumatoid arthritis based on patient withdrawal.
        Rheumatology (Oxford). 2005; 44: 1414-1421
      8. Remicade (infliximab) [prescribing information]. Centocor, Inc, Malvern, Pa2008
      9. Enbrel (etanercept) [prescribing Information]. Amgen Inc, Thousand Oaks, Calif2008
      10. HUMIRA (adalimumab) [prescribing information]. Abbott Laboratories, North Chicago, Ill2008
        • Duclos M
        • Gossec L
        • Ruyssen-Witrand A
        • et al.
        Retention rates of TNF blockers in daily practice in 770 rheumatic patients.
        J Rheum. 2006; 33: 2433-2439
        • Smith JB
        • Haynes MK
        Rheumatoid arthritis-a molecular understanding.
        Ann Intern Med. 2002; 136: 908-922
        • Panayi GS
        The pathogenesis of rheumatoid arthritis and the development of therapeutic strategies for the clinical investigation of biologics.
        Agents Actions Suppl. 1995; 47: 1-21
        • Dörner T
        Crossroads of B cell activation in autoimmunity: Rationale of targeting B cells.
        J Rheumatol Suppl. 2006; 77: 3-11
        • Edwards JC
        • 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
        • Cohen SB
        • Emery P
        • Greenwald MW
        • et al.
        Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: Results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks.
        Arthritis Rheum. 2006; 54 (for the REFLEX Trial Group): 2793-2806
        • Emery P
        • Fleischmann R
        • Filipowicz-Sosnowska A
        • 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 (for the DANCER Study Group): 1390-1400
        • Edwards JC
        • Cambridge G
        B-cell targeting in rheumatoid arthritis and other autoimmune diseases.
        Nat Rev Immunol. 2006; 6: 394-403
        • Raderer M
        • Jäger G
        • Brugger S
        • et al.
        Rituximab for treatment of advanced extranodal marginal zone B cell lymphoma of the mucosa-associated lymphoid tissue lymphoma.
        Oncology. 2003; 65: 306-310
        • Gong Q
        • Ou Q
        • Ye S
        • et al.
        Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy.
        J Immunol. 2005; 174: 817-826
        • Weng WK
        • Levy R
        Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma.
        J Clin Oncol. 2003; 21: 3940-3947
        • Cartron G
        • Dacheux L
        • Salles G
        • et al.
        Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor Fc?RIIIa gene.
        Blood. 2002; 99: 754-758
        • van der Kolk LE
        • Grillo-Lépez AJ
        • Baars JW
        • et al.
        Complement activation plays a key role in the side-effects of rituximab treatment.
        Br J Haematol. 2001; 115: 807-811
        • Barone D
        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 (Abstract): 159
        • Barone D
        TRU-015, a novel CD20-directed biologic therapy, demonstrates significant anti-tumor activity in human tumor xenograft models.
        J Clin Oncol. 2005; 23 (Abstract): 25-49
        • World Medical Association Declaration of Helsinki
        Ethical principles for medical research involving human subjects. September 24, 2008
        http://www.wma.net/e/policy/b3.htm
        (Accessed)
        • Arnett FC
        • Edworthy SM
        • Bloch DA
        • et al.
        The American Rheumatism Association 1987 revised criteria for the clas sification of rheumatoid arthritis.
        Arthritis Rheum. 1988; 31: 315-324
        • Hochberg MC
        • Chang RW
        • Dwosh I
        • et al.
        The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis.
        Arthritis Rheum. 1992; 35: 498-502
        • LeBien TW
        • Tedder TF
        B lymphocytes: How they develop and function.
        Blood. 2008; 112: 1570-1580
        • Levesque MC
        • St Clair EW
        B celldirected therapies for autoimmune disease and correlates of disease response and relapse.
        J Allergy Clin Immunol. 2008; 121: 13-21
      31. (DCTD, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Cancer Therapy Evaluation Program. Common terminology criteria for adverse events, version 3.0 [CTEP Web site])
        http://ctep.cancer.gov
        Date: August 9, 2006
        (Accessed)
        • US Food and Drug Administration
        Medical Dictionary for Regulatory Activities [MedDRA Web site]. October 3, 2008
        http://www.meddramsso.com/MSSOWeb/index.htm
        (Accessed)
        • Habermann TM
        • Weller EA
        • Morrison VA
        • et al.
        Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma.
        J Clin Oncol. 2006; 24: 3121-3127
        • Pfreundschuh M
        • Trümper L
        • Osterborg A
        • et al.
        CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: A randomised controlled trial by the MabThera International Trial (MInT) Group.
        Lancet Oncol. 2006; 7 (for the MabThera International Trial Group): 379-391
        • Ding C
        • Foote S
        • Jones G
        B-cell-targeted therapy for systemic lupus erythematosus: An update.
        BioDrugs. 2008; 22: 239-249
        • Lee RW
        • D'Cruz DP
        Novel therapies for anti-neutrophil cytoplasmic antibody-associated vasculitis.
        Drugs. 2008; 68: 747-770
        • Garvey B
        Rituximab in the treatment of autoimmune haematological disorders.
        Br J Haematol. 2008; 141: 149-169
        • Dalakas MC
        Invited article: Inhibition of B cell functions: Implications for neurology.
        Neurology. 2008; 70: 2252-2260
        • Lobo ED
        • Hansen RJ
        • Balthasar JP
        Antibody pharmacokinetics and pharmacodynamics.
        J Pharm Sci. 2004; 93: 2645-2668
        • Burge D
        • Shu C
        • Martin RW
        • et al.
        TRU-015, a Small Modular ImmunoPharmaceutical (SMIP) drug candidate directed against CD20, demonstrates clinical improvement in subjects with rheumatoid arthritis.
        Arthritis Rheum. 2006; 54: S230
        • Barone D
        • Baum P
        • Ledbetter J
        • et al.
        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
        • Bugelski PJ
        • Treacy G
        Predictive power of preclinical studies in animals for the immunogenicity of recombinant therapeutic proteins in humans.
        Curr Opin Mol Ther. 2004; 6: 10-16

      Article info

      Publication history

      Accepted: August 27, 2008

      Identification

      DOI: https://doi.org/10.1016/j.clinthera.2008.10.017

      Copyright

      © 2008 Excerpta Medica Inc. All rights reserved. Published by Elsevier Inc.

      ScienceDirect

      Access this article on ScienceDirect

      The content on this site is intended for healthcare professionals.


      We use cookies to help provide and enhance our service and tailor content. To update your cookie settings, please visit the Cookie Preference Center for this site.
      Copyright © 2023 Elsevier Inc. except certain content provided by third parties.


      RELX