GlaxoSmithKline has had to halt a Phase IIb clinical trial of its HIV entry inhibitor aplaviroc after severe liver toxicity was experienced by two patients in the study.

GSK had high hopes for aplaviroc, formerly known as 873140, as it used a different mode of action to currently-available HIV treatments and therefore unlikely to show any cross-resistance. The company has stopped the Phase IIb trial of the drug in treatment-naïve patients, although it is continuing a Phase III study in patients who have previously been treated with other antiretrovirals, with the proviso that they are carefully monitored for toxicity.

As a CCR5 antagonist, the drug blocks HIV from getting into host cells a similar but distinct mechanism from Roche and Trimeris’ already-approved fusion inhibitor Fuzeon (enfuvirtide). However, aplaviroc is orally-bioavailable - unlike Fuzeon which requires twice-daily subcutaneous injections - and was expected to be a cheaper option as it is easier to synthesise. The discovery of such a serious side effect was an unexpected blow, because GSK and other companies developing this type of drug ˆ such as Pfizer and Schering-Plough ˆ had been bullish about the expected safety profile of the class [[04/05/05g]].

Aplaviroc’s problems lengthen Pfizer’s lead in the race to bring a CCR5 inhibitor to market, as its orally-available maraviroc (UK-427,857) is already well into a Phase III clinical programme, while Schering-Plough’s SCH-417690 candidate is in Phase II. GSK said it was still committed to its compound, but its commercial potential has likely been hamstrung by the emergence of the toxicity issue. Analysts have predicted that the first CCR5 antagonist to reach the market could rapidly achieve sales in excess of $500 million a year.

In addition to aplaviroc, GSK’s HIV pipeline also includes 640385, a next-generation protease inhibitor in Phase II development and 695634, in Phase II development as a novel non-nucleoside reverse transcriptase inhibitor. Both compounds are being evaluated for treatment of those patients whose virus has become resistant to multiple antiretroviral drugs.

GSK licensed aplaviroc from Japan’s Ono Pharmaceuticals in 2003 [[16/02/04f]].