RESULTS OF A RANDOMIZED, PLACEBO CONTROLLED, DOUBLE BLIND PHASE 1/2 CLINICAL TRIAL (RCT) TO ASSESS THE SAFETY AND TOLERABILITY OF LJP 1082 IN PATIENTS WITH ANTIPHOSPHOLIPID SYNDROME

Arash Horizon, Michael H. Weisman, Daniel J. Wallace, Joan T. Merrill, Matthew D. Linnik, Keith A. Cockerill, Richard Furie

Introduction:
A phase 1/2 clinical trial was conducted to assess the safety, tolerability and pharmacokinetics of LJP 1082, a B cell toleragen designed to reduce levels of pathogenic antibodies in antiphospholipid syndrome (APS). The dominant autoantibodies in APS are directed to domain 1 of beta-2-glycoprotein I (beta-2-GPI) and are believed to cause a hypercoagulable state that increases the risk of thrombotic events and recurrent fetal loss. LJP 1082 is a tetravalent conjugate of recombinant human domain 1 that has been shown to reduce domain 1 specific antibodies and levels of antigen-specific antibody producing B cells in rodents (2003, Int. Immunopharmacol., 3:1667-1675).

Trial design:
Dose levels: 20 patients in groups of 4-5 received 1, 3, 10, 50 or 200 mg LJP 1082 as a single intravenous infusion. One patient in each group received placebo.
Inclusion criteria: Males or females, ages 18-55, with antibodies to beta-2-GPI greater than 20 standard IgG units.

Exclusion criteria:
Patients were excluded who had a thrombotic event within 6 months prior to screening, two thrombotic events within 12 months prior to screening, an INR > 3 at screening or a change in anticoagulant treatment within 2 weeks prior to dosing.
Safety assessments: During the 30-day follow-up period, safety assessments included standard hematology, urinalysis, serum chemistry, vital signs, and ECGs. Trial medication levels, complement levels, circulating immune complexes, PT, aPTT, antibody levels and T cell responses to LJP 1082 were also measured.

Preliminary safety results:
The frequency of adverse events was not different in the treatment and placebo groups, and there were no serious adverse events. The study detected no changes in complement proteins or immune complexes (data not shown), and there was no detectable activation of patient T cells related to administration of LJP 1082.

Plasma drug levels:
Initial plasma levels of LJP 1082 in the 200 mg dose group ranged from 20 to 30 micrograms per mL. The time to 50% of initial levels was approximately 5-6 hours, and the elimination half-life was estimated at approximately 10-12 hours.
Antibody levels: Circulating antibodies from treated patients bound to LJP 1082 in a dose-dependent manner. Patients treated with 200 mg showed the highest level of reactivity with LJP 1082. Following a single dose of LJP 1082, there were no immediate changes in anticardiolipin antibodies or anti-beta-2-GPI antibodies.

Conclusion:
LJP 1082 appeared to be well tolerated in patients with antibodies to beta-2-GPI following a single intravenous dose up to 200 mg. Although the single-dose trial design was not intended to measure B cell tolerance, the observed binding of LJP 1082 to target antibodies was consistent with its intended pharmacological activity. The results of this trial support the further development of a B cell toleragen to treat Antiphospholipid Syndrome.

Presented at the
67th Annual Meeting of the American College of Rheumatology
Orlando, FL
October 23-28, 2003