Late-Breaking Abstracts
J. Becker, M.D., et al. A Multi-center, randomized, double-blind, placebo controlled study to evaluate the safety and preliminary clinical activity of multiple doses of CTLA4Ig and LEA29Y administered intravenously to subjects with rheumatoid arthritis.
CTLA4Ig and LEA29Y are receptor immunoglobulin fusion proteins that bind to B7 receptors on antigen presenting cells, thereby preventing T-cell proliferation and cytokine production. This study assessed the safety and preliminary efficacy of these medications in subjects with rheumatoid arthritis.
Methods: CTLA4Ig, LEA29Y (0.5, 2 or 10 mg/kg doses) or placebo were administered IV to 214 subjects (25-32 per treatment group) on days 1, 15, 29 and 57 and were evaluated on day 85. The primary endpoint was the proportion of subjects meeting the ACR20 criteria. Subjects at baseline had a mean disease duration of 3.4 years and had failed at least one DMARD. Stable NSAIDs or steroids were permitted (< 10 mg qd) and concomitant DMARDS were prohibited.
Results: CTLA4Ig and LEA29Y were well tolerated at all dose levels. ACR20 responses on day 85 increased dose-dependently: 23%, 44% and 53% in CTLA4Ig-treated subjects, and 34%, 45%, 61% in LEA29Y-treated subjects at 0.5, 2.0, 10 mg/kg, respectively - compared to 31% for placebo. However, the only statistically significant difference from placebo was at the 10 mg/kg dose of LEA29Y for ACR20, and at the 2 mg/kg dose of CTLA4Ig for ACR70. Dose-dependent trends for decrease in inflammatory markers such as CRP, IL-2 receptor, and ICAM-1 were also observed.
Conclusions: CTLA4Ig and LEA29Y were well tolerated and appear to have clinical activity in RA. Further studies are in progress.
Richard Furie, M.D., et al. A Single Dose, Placebo-Controlled Double-Blind, Phase I Study of Humanized Anti-C5 Antibody h5G1.1 in Patients with Systemic Erythematosus
The activation of complement within the joint causes cleavage of C5 into C5a and C5b-9 which mediate multiple proinflammatory responses. C5a, an anaphylatoxin and chemotaxin, localizes elements of the inflammatory response, degranulates neutrophils thereby causing release of free oxygen radicals and prostaglandins, and also stimulates Il-1 and Il-6 production. In contrast, C5b-9 is instrumental in the lytic pathway.
This study assessed the safety, tolerability, efficacy, pharmacokinetics, and biological effects of h5G1.1 a high affinity humanized monoclonal antibody directed against C5 which inhibits cleavage into proinflammatory products C5a and C5b-9, in patients with SLE.
Methods: 24 SLE patients were given a single I.V. dose of study medication (placebo or 0.1, 0.3, 0.75, 2.0, 4.0, 8.0 mg/kg of drug) and followed for safety, pharmacokinetics, pharmacodynamics, and efficacy. The primary outcome was duration of greater than 80% C5 inhibition.
Results: h5G1.1mab was safe and well tolerated in SLE patients. Duration of response of greater than 80 % C5 inhibition was examined for all doses. Placebo and 0.1-0.75 mg/kg did not inhibit complement activity. At a dose of 2.0mg/kg complement activity was inhibited for 24 hours but returned to baseline at 2 days. A dose of 4.0 mg/kg produced C5 inhibition for 5 days. A single dose of 8 mg/kg suppressed complement serum activity for more than 10 days. Complement inhibition returned to baseline at 14 days at the two highest doses. There were no significant antibody response nor significant differences observed in clinical score (SLEDAI) or physician global assessments between all doses of drug and control. Patient disease assessments displayed an improvement trend in the 8mg/kg dose group at day 28 and day 56. Additionally, there were no clinically significant adverse events (including infections) that demonstrated dose dependent trends.
Conclusions: h5G1.1mab is safe and well tolerated in SLE patients. There was no significant antibody responses to the infused antibody. No significant changes were observed in laboratory values, clinical parameters or SLEDAI.
J. Peterson, Ph.D. An Extended Phase I/II Study of a Novel Non-Depleting Fully Human Anti-CD4 Monoclonal Antibody (HuMax CD4) in Rheumatoid Arthritis Patients Treated with Methotrexate
Circulating T cells contribute significantly in the pathogenesis of rheumatoid arthritis (RA). In RA, one of the most prominent infiltrating T cells in the synovium is the CD4+ T cell. CD4+ T cells become activated when presented with an antigen by Class II Major Histocompatibility Complex (MHC) molecules. Activated T cells ultimately produce an inflammatory immune response resulting in joint destruction. A CD4 monoclonal antibody may present a novel therapeutic agent to suppress inflammation in RA.
Objective: To assess the safety and tolerability of a fully humanized monoclonal antibody (IgG1-k, HuMax-CD4) and to study CD4 receptor occupancy, CD4+ T cell counts, and plasma levels of HuMax-CD4) in patients with active rheumatoid arthritis treated with methotrexate.
Methods: 10 subjects with active RA received a single subcutaneous infusion of HuMax-CD4 (4.0mg/kg) in combination with concurrent stable treatment of methotrexate (> 12.5mg/week) with a 28 day follow-up. CD4 receptor occupancy with competing and non-competing anti-CD4 antibodies was obtained by double flourescence staining.
Results: Near maximal saturation of CD4 receptors was observed between day 1 and 7 and peaked on day 2 with values ranging from 79% to 92% in all patients. No significant changes were observed in the actual number of CD4+ cells. Plasma levels of HuMax peaked on day 2, ranging from 2.3 to 3.3 mg/ml. Reductions in clinical assessment of swollen and tender joints and the physician global assessment of disease activity were observed with medians of 54%, 38%, and 54% respectively. A 20% ACR20 response was obtained. Mild adverse events unrelated to treatment were reported.
Conclusions: A single infusion of HuMax CD4 at 4.0mg/kg was well tolerated. Circulating CD4+T cells are not depleted in RA patients with concomitant treatment with methotrexate.
