A non-nucleoside reverse transcriptase inhibitor (NNRTI) called capravirine has been pulled from clinical studies pending safety checks, following the discovery that the drug caused vasculitis (inflammation of blood vessels) in dogs. Vasculitis may cause severe damage to the tissues supplied by inflamed blood vessels, because blood cannot reach the tissues.
So far, no cases of vasculitis have been reported in people taking capravirine, but the US Food and Drug Administration has ordered Agouron/Pfizer to stop several studies of the drug until safety checks can be carried out on all patients receiving the drug. These studies inlcude protocol 504, which has already recruited treatment-naive patients in the UK. However, patients currently receiving capravirine in study 509 who have undetectable viral load will be allowed to continue taking the drug if they wish. This study is comparing background therapy with two nucleoside analogues with or without capravirine in NNRTI-experienced individuals. This study is also recruiting patients in the UK.
If capravirine is found to have unacceptable toxicities, it will remove the only salvage option in this class of drugs for NNRTI-experienced individuals on the near horizon, and bring into sharp focus the need for careful use of NNRTIs in clinical practice in order to maximise the utility of this class of drugs. Failure of one NNRTI leads to cross-resistance to all currently available NNRTIs, and even capravirine is likely to be active only against viruses with resistance to efavirenz. Resistance to nevirapine (usually characterised by a mutation at codon Y181C) would render capravirine useless.
For Agouron-Pfizer, this is a depressing development. The company had to scrap development of new protease inhibitor, AG-1776, last year, and a large clinical endpoint study of Remune, the therapeutic vaccine being developed in partnership with Immune Response Corporation, showed no benefit in a controversial study published in the New England Journal of Medicine last year.