MediGene AG (Martinsried/Munich, Germany), a publicly-held biotechnology company with subsidiaries in Oxford, UK and San Diego, US, and focused on drugs in three therapeutic areas: autoimmune diseases, skin diseases, and cancer, announced that an ongoing phase I study investigating the bioavailability of a new tablet formulation of RhuDex^®, an orally administered candidate for the treatment of rheumatoid arthritis (RA), has been placed on clinical hold after one study participant suffered a heart problem some days after a scheduled treatment of RhuDex. The patient was subsequently treated in hospital and discharged a few days later; the volunteer died several days after discharge. Investigations into the cause of death will be carried out, but it is currently unclear whether there is any correlation between the death and the drug administration.

Prior to the event, the company reported that it had achieved its objectives in a phase IIa clinical trial of the drug for the treatment of RA. In addition to positive safety and tolerability data and the demonstration of acceptable adsorption after oral administration, first indication of biological activity of RhuDex was observed. The 2-week placebo-controlled pilot trial was conducted in patients suffering from RA, who were simultaneously treated with methotrexate (MTX). After an increase of the plasma level after treatment with RhuDex 100 and 200 mg, a saturation of the plasma concentration was reached with RhuDex 400 mg, thereby achieving the primary trial objective. The drug showed good tolerability in all 29 patients and at all dosages administered. No interaction between the drug and MTX was observed. A new pharmaceutical form of the drug as a tablet had been developed and its bioavailability was under investigation in the ongoing phase I study.

So far, about 80 individuals have been treated with RhuDex and, according to MediGene, no comparable cardiac events occurred in other study subjects or in previous clinical studies. No signs of cardiac effects due to the drug were observed in the preclinical programs. Eleven volunteers in the current phase I study showed only mild side effects like headaches.

The data regarding pharmacokinetics and bioavailability obtained in the phase IIa trial are hoped to form the basis of a comprehensive phase II trial of RhuDex scheduled for initiation in 2009. In the planned phase II trial with the new tablet formulation, patients will be treated over a 3-month period in which efficacy data will be collected.

RhuDex is being developed as the first orally administered and specifically effective disease-modifying antirheumatic drug. RhuDex, an active small molecule CD80 (B7-1) antagonist, inhibits T-cell activation by blocking the “second signal” coreceptor binding event involving CD80 expressed in chronically diseased tissues and CD28 on the T-cell, thus blocking the release of inflammatory cytokines such as TNFα, IL-1β, IL-2, and IFNγ. RhuDex has a half-life of ~16 hours.

The drug has a similar mode of action to the recently approved biological Orencia® (abatacept, Bristol-Myers Squibb Co). Orencia is a soluble fusion protein, having an apparent molecular weight of 92 kd, that consists of the extracellular domain of human cytotoxic T-lymphocyte-associated antigen 4 linked to the modified Fc (hinge, CH2, and CH3 domains) portion of human immunoglobulin G1. Also a selective costimulation modulator, Orencia inhibits T-cell activation by binding to CD80 and CD86 (B7-2), thereby blocking interaction with CD28. However, unlike RhuDex, Orencia is dosed by parenteral administration.