GSK closes phase 3 studies of its CCR5 inhibitor aplaviroc and terminates development programme

In the last issue of HTB, we reported that GSK suspended naive studies of their CCR5 inhibitor aplaviroc (GW873140) due to two cases of serious but non-fatal hepatotoxicity. On 25 October the company issued a press announcement that all phase 2b and 3 trials including those in treatment experienced patients are also to be terminated.

Phase 3 development started in July 2005 for the treatment of HIV-1 infection in treatment-experienced patients. In September 2005, all phase 2b clinical trials in HIV treatment-naive patients, as well as studies in healthy volunteers, were terminated due to cases of severe hepatotoxicity. Phase 3 studies in treatment-experienced patients with multi-drug resistant virus and limited treatment options remained open, although further enrollment was on hold while data from the phase 2b studies were reviewed. Patients who were already in the phase 3 studies had the option to continue therapy and were closely monitored for any adverse events during that time.

GSK recently received a report of a patient in one of the phase 3 trials who experienced elevated liver enzymes (AST, ALT) and total bilirubin. Based on a review of this case in the context of the previous reports from the phase 2b studies, GSK has stopped all phase 3 studies of aplaviroc. No further clinical studies of the compound are planned at this time.

It is GSKs intention to stop therapy with aplaviroc for all current trial participants. However, treatment-experienced patients who are currently on aplaviroc and receiving clinical benefit, as determined by their physician, may elect to continue aplaviroc therapy until an alternative regimen can be devised or until they are no longer deemed to be deriving benefit from the drug. These patients will continue to be monitored closely for signs or symptoms of liver toxicity, and elevations in liver function tests. Clinical trial investigators and their Institutional Review Boards or Ethics Committees have been notified of the situation and have received instructions for transitioning of patients participating in the Phase 3 trials.

GSK is actively reviewing the aplaviroc safety data, and follow-up on all patients is ongoing.

Comment

An additional unscheduled oral presentation at the EACS conference in Dublin, enabled GSK to present a more detailed review of the details behind the decision to stop development of aplaviroc.

Four cases of hepatic toxicity, defined by dramatic increases in ALT levels, were complicated by similar increases in bilirubin. According to Hys law, when both ALT and bilirubin increase in the same patient, there is a 10-50% risk of the reaction being fatal. Fortunately, none of the cases in the GSK study were fatal.

After the GSK presentation, and in response to a question from Stefan Mauss, a spokesperson from Pfizer read a short pre-prepared statement relating single case of hepatic toxicity associated with maraviroc (the Pfizer CCR5 inhibitor). The limited details released about this case, including it being a single case from over 1000 patients exposed to the compound, that it involved a recent coinfection with hepatitis C, and the use of other hepatic-toxic drugs. This suggests that similar safety concerns to the GSK compound may not be occurring, creating the possibility that this may be a drug-specific rather than a class effect.

Source: GSK press release GSK terminates patient enrollment for Phase 3 studies of investigational HIV entry inhibitor aplaviroc (GW873140). 25 October 2005.