GlaxoSmithKline has halted clinical trials of its first-in-class HIV drug after cases of hepatotoxicity was discovered in treatment-naïve patients. The setback does not mean the end of development for this drug candidate but suggests Glaxo has lost significant ground in its race with rivals Pfizer.
CCR5 antagonists are a new class of anti-HIV drugs that target a stage in the HIV lifecycle. The CCR5 co-receptor was considered an attractive target for HIV therapy, as it is the major co-receptor for the viral infection of immune cells.
The company announced that an international phase III study of aplaviroc (GW873140) had been halted due to reports of severe hepatotoxicity in phase IIb studies.
GSK, who are keen to realise the potential of this drug, is still offering treatment-experienced patients the option of continuing in its Phase III study, but with closer monitoring for signs of liver toxicity.
The news that two out of 250 treatment-naïve (who have not received other HIV therapies) patients given Glaxo's aplaviroc had liver problems is unexpected, since one of the main advantages of CCR inhibitors was its low toxicity.
A statement by GSK said that clinical trial investigators and their IRBs had been notified and instructions were given as to treatment of the patients involved.
The statement also said that a protocol amendment for Phase III studies involving treatment-experienced patients would become available within the next week and would include a revised informed consent form.
"While we are stopping our work in treatment-naïve patients, we are proceeding cautiously with treatment-experienced HIV patients who need new treatment options," said Lynn Marks, senior vice president, GSK Medicine Development Centre, Infectious Diseases.
"We are working closely with regulatory authorities, the clinical trial sites and the patients involved in these studies," she added.
GSK's decision to continue its studies on the CCR5 inhibitor is seen by many as a high-risk manoeuvre. Currently, there is no definitive data available on the risk that a CCR5 inhibitor may cause a switch to the more harmful X4 virus in seriously immunocompromised patients.
GSK's other HIV treatment, tipranavir/ritonavir, has also suffered from tolerability problems, having also displayed a risk of hepatotoxicity.
All things considered, phase III safety data is likely to be much more scrutinised before aplaviroc obtains regulatory approval to proceed further.
Pfizer is already at a more advanced stage with its similar CCR inhibitor drug, maraviroc. The new drug can be given as a tablet and works by locking a cellular doorway, or co-receptor, called CCR5.
The idea for the drug class came from the observation that people with mutated CCR5 can resist HIV infection, even after exposure to numerous high-risk sexual partners.
Most existing HIV drugs work inside the body's immune cells, after the virus has infected. They can cause anaemia, nerve pain, diarrhoea, fat wasting and organ damage - leading researchers to study other approaches.
Such is the potential of CCR5's that industry analysts estimate that a successful candidate should generate sales of $500-700 million (€412 million - €577 million) a year, with the first products likely to reach the market in 2007 or 2008.