Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement

Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.


Results from a Phase I Study of MLTA3698A, a Novel Anti-Lymphotoxin-a Monoclonal Antibody: Safety, Tolerability and Biologic Activity in Patients with Active Rheumatoid Arthritis.

Emu2,  Brinda, Luca3,  Diana, Offutt3,  Carolyn, Grogan3,  Jane, Davis3,  John, Rojkovich1,  Bernadette, Williams3,  Marna

Budai Irgalmasrendi
Genentech, Inc., South San Francisco, CA
Genentech, Inc.

Background:

Lymphotoxin (LT)-a is a cytokine transiently expressed by subsets of activated lymphocytes that are implicated in the pathogenesis of RA/autoimmunity including T-helper cells (Th1, Th17) and B cells. The biologic agent MLTA3698A is a humanized monoclonal antibody directed against the cytokine LTa, and has several distinct mechanisms of action, including blocking soluble and membrane-bound LTa from interacting with its receptors and selectively depleting subsets of activated immune cells. We report a randomized, double-blind, placebo-controlled trial designed to assess safety, tolerability, pharmacokinetics, impact on biomarkers, and preliminary evidence of biologic activity after single and multiple doses of either intravenous or subcutaneous administration of MLTA3698A in RA patients.

Methods:

The first stage of the study consisted of a single dose escalation of MLTA3698A or placebo at 6 doses (0.3 IV, 1.0 IV, 1.0 SC, 3.0 IV, 3.0 SC, and 5.0 mg/kg; n=30) in patients with stable RA. The second stage of the study consisted of a multiple dose escalation phase in which patients with active RA (on stable regimen for RA, with >= 5 swollen joints, >5 tender joints and CRP >= 1.0) received 3 doses of MLTA3698A or placebo every 2 weeks (1.0 SC, 3.0 SC, or 5.0 IV mg/kg; n=35). Safety and tolerability were assessed in patients in both single and multiple dose escalation stages. CXCL-13, a downstream chemokine in LTa signaling pathway, was measured prior to and after dosing. Clinical activity endpoints were measured at multiple time points in patients in the multiple dose escalation stage.

Results:

Baseline characteristics of patients who received MLTA3698A or placebo were similar with respect to demographics and RA disease status (median age of 57 years, median CRP of 1.21, and median DAS28-CRP of 4.21). The majority of adverse events were mild to moderate. There were no serious adverse events or dose-limiting toxicities in the trial. There were no serious infections or notable changes in peripheral lymphocyte subsets. Pharmacokinetic profiles were linear and clearance was independent of dose. Substantial reductions in levels of serum CXCL-13 were observed. Preliminary evidence of clinical activity was seen in the multiple dose stage as evidenced by ACR20, ACR50, and ACR70 response rates as well as reduction in DAS28CRP scores and C-reactive protein (CRP) levels.

Conclusions:

Blockade of LTa pathway is a promising mechanism of action for the treatment of RA. MLTA3698A was generally well tolerated and demonstrated preliminary evidence of clinical activity.

To cite this abstract, please use the following information:
Emu, Brinda, Luca, Diana, Offutt, Carolyn, Grogan, Jane, Davis, John, Rojkovich, Bernadette, et al; Results from a Phase I Study of MLTA3698A, a Novel Anti-Lymphotoxin-a Monoclonal Antibody: Safety, Tolerability and Biologic Activity in Patients with Active Rheumatoid Arthritis. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1122
DOI: 10.1002/art.28889

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