Clinical Trials - Thrombosis Human Trials

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Clinical Trials :: Thrombosis Clinical Trial

Antibody-mediated Thrombosis Candidate in Human Clinical Trials

In October 2002, La Jolla Pharmaceutical completed a Phase I/II Clinical trial of its second development-stage Toleragen, LJP 1082, for the treatment of antibody-mediated thrombosis, a life-threatening blood-clotting disorder.

Antibody-mediated thrombosis, also known as the Antiphospholipid Syndrome (APS), is an autoimmune disease afflicting more than two million patients in the U.S. and Europe. These patients face an increased risk of blood clots that can result in stroke, myocardial infarction, deep-vein thrombosis, recurrent fetal loss, and post-operative complications following cardiovascular surgery. The disease is often discovered in younger patients who suffer a heart attack or stroke, but otherwise lack the typical risk factors for these disorders.

In this disease, pathogenic B cells produce high levels of antiphospholipid antibodies that target beta 2-glycoprotein 1 (beta 2 GP1), a key blood protein. These antibodies inhibit the inactivation of a blood-clotting protein called Factor Va, which can dramatically accelerate clotting. Antiphospholipid antibodies are found in more than 20% of all stroke patients, about 10% of heart-attack patients, and in approximately 25% of all deep-vein thrombosis and recurrent fetal-loss patients.

Initial results from Phase I/II clinical trial presented at the American College of Rheumatology Annual Meeting October 27, 2002

The Phase I/II trial was a randomized, placebo-controlled study that was designed to evaluate the safety and activity of a single dose of LJP 1082. Based on an initial assessment of the trial data, the drug was well-tolerated at all five dose levels. LJP 1082 had an elimination half-life of at least 12 hours following intravenous administration. Following treatment with a single 50 mg or 200 mg dose, antibodies to LJP 1082 were reduced in some patients.

In total, 20 patients with a history of antibody-mediated thrombosis participated in the trial period. All adverse events observed were categorized as mild to moderate and deemed to have no or an unlikely relationship to study drug. The adverse event profiles appeared similar between drug-treated and placebo-treated groups. There were no serious adverse events. No significant increase in circulating immune complexes, changes in complement protein C3 or activation of patient T cells was observed following drug treatment.

Even though there were a small number of patients in the study, there was an apparent dose-dependent response following drug treatment. Patients receiving higher doses of LJP 1082 had larger reductions in antibodies to LJP 1082. In the 50 and 200 mg treatment groups, there was an apparent correlation between the level of reduction and the affinity of the patient's antibodies for drug. Most patients had antibodies that were specific for the first domain of the target protein, beta 2 GP1, which is the epitope presented on LJP 1082.

This study is the first of several that may be required to establish appropriate dose regimens and the observed reductions may not be large enough to affect patient health or reduce antibodies to beta 2 GP1in a majority of patients. Additional analyses are ongoing. Potential drug interference in some of the antibody assays is also being evaluated. This study was not designed to evaluate the ability of LJP 1082 to tolerize B cells that produce antibodies to beta 2 GP1 and additional studies will be needed.

Trial Design

In the Phase I/II trial, five different groups, each consisting of four or five patients, were treated with a single intravenous dose of LJP 1082 of 1, 3, 10, 50 or 200 mg and then monitored for 30 days. One patient in each group received placebo. In order to participate in the trial, patients were required to have elevated levels of antibodies to beta 2 GP1, the target of the antibodies involved in antibody-mediated thrombosis. Standard safety assessments including physical exams, lab values and vital signs, and immunology specific measurements were taken over 30 days following a single dose of LJP 1082.