Abetimus: Abetimus sodium, LJP 394

Abetimus [Abetimus sodium, LJP 394, Rentol, Riquent] is a synthetic Toleragen molecule consisting of four double-stranded oligodeoxyribonucleotides attached to nonimmunogenic polyethylene glycol, a proprietary carrier platform. It was originated by La Jolla Pharmaceuticals. Abetimus is an immunomodulating agent that induces tolerance in B cells directed against double-stranded DNA (dsDNA). It does this by cross-linking surface antibodies. These antibodies are thought to be responsible for lupus nephritis, a chronic kidney disease that develops in patients with systemic lupus erythematosus. A phase III trial of abetimus was completed in December 2002. La Jolla Pharmaceuticals previously established two licensing agreements for abetimus, which have since been terminated. One of the agreements was with Leo Pharmaceutical Products of Denmark. The company was licensed rights to abetimus covering Europe and the Middle East. The other agreement was with Abbott Laboratories. Abbott returned all rights to abetimus to La Jolla Pharmaceuticals in September 1999 based on the results of an analysis of the phase II/III trial of abetimus in lupus patients with a history of renal disease. A phase III trial, named "PEARL" (Program Enabling Antibody Reduction in Lupus), has been conducted in the US in patients with lupus nephritis. It enrolled 317 patients with a history of lupus who were treated with a weekly dose of abetimus 100mg or placebo. The trial was completed in December 2002 and preliminary results were reported in February 2003. PEARL was designed to determine whether abetimus can significantly delay renal flares and delay the need for treatment with high-dose corticosteroids and/or cyclophosphamide in patients with high affinity IgG antibodies to the double-stranded oligonucleotide epitope in abetimus. Patients with high-affinity antibodies, were selected using a surface plasmon resonance (SPR)-based pharmacoproteonomics assay provided by Biacor International. Following the completion of PEARL in December 2002, La Jolla Pharmaceuticals initiated an on-going, open-label, follow-on trial. All patients who had completed PEARL were eligible to enroll and receive weekly treatment with abetimus. However, in April 2003, La Jolla Pharmaceuticals announced that it was closing this trial, which was designed to collect additional long-term safety data, to conserve resources for the continued development of the drug. Previously, La Jolla Pharmaceuticals and Abbott initiated a phase II/III trial of abetimus in more than 200 patients with lupus nephritis. However, this trial was discontinued in May 1999 because the primary end-point (time to renal flare) was much shorter than expected. After the trial was halted, further analysis of trial data using a new blood test to measure the strength of the binding between abetimus and a patient's antibodies to dsDNA was conducted. The additional analysis showed that the number of renal flares in the high-affinity patients (responders) treated with abetimus was less than half of the number of renal flares in high-affinity patients treated with placebo. Responders also showed a significant reduction in the use of high-dose corticosteroids and cyclophosphamide. Being able to screen patients to identify those likely to respond to therapy lead La Jolla Pharmaceuticals to initiate PEARL after Abbott's withdrawal from the drug. It is believed that screening patients will help increase the cost-effectiveness of clinical development. In September 2000, the US FDA granted orphan drug status for abetimus in the treatment of lupus nephritis. The European Commission followed suit in November 2001, granting orphan drug status for abetimus in the EU.