GSK halts chemokine inhibitor trial due to safety fears

Keith Alcorn
Published: 16 September 2005

Glaxo SmithKline has terminated a major study of its experimental CCR5 inhibitor aplaviroc following reports of severe hepatotoxicity in phase IIb studies involving treatment-naïve patients.

The company announced yesterday that an international phase III study of aplaviroc (GW873140) has been halted, but that studies in treatment-experienced patients will continue, subject to close monitoring of study participants. The press statment did not address the issue of whether serious liver enzyme elevations and bilirubin elevations resulted in clinical hepatitis or liver damage, nor how many events were reported.

The toxicity is unexpected, since companies that are developing CCR5 inhibitors have been optimistic about the toxicity profile of this drug class. Although CCR5 receptors are present throughout the body, people who are born without these receptors do not seem to suffer any adverse consequences, and GSK has been keen to emphasise that aplaviroc alters the way in which the CCR5 receptor presents itself to the outside world, rather than blocking it completely. This should prevent HIV entry without impeding any other processes for which the receptor might prove essential.

According to a statement issued yesterday by GSK, treatment-experienced patients already enrolled in the Phase III studies may elect, in discussion with their physician-investigator, to continue on their study medication, but will be monitored closely for signs or symptoms of hepatotoxicity and/or elevations in liver function tests. Clinical trial investigators and their IRBs have been notified of the situation and how to handle the treatment of the patients involved. A protocol amendment for Phase III studies involving treatment-experienced patients will be forthcoming in the next week and will include a revised informed consent form.

"GSK is committed to excellence in the care of individuals with HIV infection, and we are taking all necessary steps to protect the safety and health of these clinical trial participants," said Lynn Marks, MD, Senior Vice President, GSK Medicine Development Centre, Infectious Diseases. "While we are stopping our work in treatment-naïve patients, we are proceeding cautiously with treatment-experienced HIV patients who need new treatment options. We are working closely with regulatory authorities, the clinical trial sites and the patients involved in these studies. Patient safety remains our major focus."

Although GSK says it is committed to pursuing aplaviroc research in treatment-experienced patients who need new treatment options, the economic viability of aplaviroc as a product is likely to be an ongoing concern for the company. With no definitive data yet available on the risk that a CCR5 inhibitor may drive a switch to the more harmful X4 virus in seriously immunocompromised patients, continuation of phase III studies is a high risk strategy. Given the existing tolerability problems of other salvage products (in particular the risk of hepatotoxicity associated with tipranavir/ritonavir), phase III safety data are likely to be rigourously scrutinised before aplaviroc could be licensed.

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