ZymoGenetics, Inc. and Serono announced favourable results from a phase 1b clinical trial with TACI-Ig in 73 patients with rheumatoid arthritis (RA), recently presented at the 7th Annual European Congress of Rheumatology (EULAR).
TACI-Ig is a soluble fusion protein that neutralizes molecules implicated in the pathogenesis of several autoimmune diseases. TACI-Ig appeared to be well tolerated across the full range of dose levels and schedules tested. Clear biologic effect was observed as patients showed schedule and dose dependent decreases in the levels of immunoglobulin (Ig) and serum rheumatoid factor levels.
Although this study was not specifically designed to evaluate efficacy, encouraging trends were observed in ACR and DAS 28 scores, commonly used measurements of clinical benefit. Based on these promising results, ZymoGenetics and Serono expect to begin the phase 2 clinical programme of TACI-Ig in patients with RA in the second half of 2006.
In an oral presentation, Alain Munafo, Ph.D., Senior Scientific Director of Serono, reported that TACI-Ig appeared to be well tolerated in patients with moderate-to-severe RA. The most common adverse event was a generally mild injection site reaction affecting approximately 40% of the patients. There were no serious adverse events reported. No patients formed detectable antibodies to TACI-Ig, and the patients' vaccination immune status did not appear to be compromised by the drug.
TACI-Ig demonstrated clear biological activity, with schedule and dose-dependent reductions of immunoglobulin levels in line with the proposed mechanism of action. In a cohort that received seven doses of TACI-Ig over a three-month period, patients showed:
Reductions of several biomarkers typically found in RA patients, including: - IgM, IgA and IgG reductions of 54%, 37% and 21% respectively; Reduction of peripheral blood B-cell levels with a maximum decrease of 30-40% 40-45% reduction of IgM-RF, IgA-RF and IgG-RF Trends toward improvement of the ACR and DAS 28 scores commonly used to measure disease severity and effects of treatment.
In a separate poster presentation, Ivan Nestorov, Ph.D., Scientific Fellow of ZymoGenetics, reported that there was a well-defined relationship between TACI-Ig exposure and immunoglobulin response. IgM levels were found to be the most responsive to TACI-Ig exposure, followed respectively by IgA and IgG levels. Dosing frequency seemed to play as important a role as dose level in the response of the three biomarkers.
The primary objective of the phase 1b study was to determine the safety and tolerability of TACI-Ig in RA patients and to examine the relationship between TACI-Ig dose and schedule with markers of biologic and disease activity. The trial enrolled adult male and female patients with active, moderate-to-severe RA. Patients received single or multiple doses of either TACI-Ig or placebo for a maximum period of three months.