August 17, 2006
Brecanavir (formerly known as GW640385) is an HIV protease inhibitor (PI) in phase 2b clinical development by GlaxoSmithKline (Glaxo). It has shown powerful antiviral activity against both wild-type and highly drug-resistant viruses. This and other newly approved PIs, such as tipranavir (TPV, Aptivus) and TMC114 (darunavir, Prezista), are really novel in that they belong to a non-peptidic PI subclass. These non-peptidic compounds tend to bind tightly to the HIV protease enzyme, even in the presence of highly drug-resistant virus, thereby increasing their potency.
One of the main attributes of brecanavir is that it may be used at a relatively low dose, which could potentially translate into fewer side effects. However, brecanavir still needs to be boosted with ritonavir (RTV, Norvir). In previously presented in vitro studies, the potency of brecanavir against highly resistant isolates was in the femptomolar range, which is tens to hundreds of times less than that of other conventional PIs. Another interesting attribute that will make this drug attractive to practitioners is the fact that brecanavir does not appear to inhibit or induce the cytochrome P450 CYP3A4 protein, which may potentially translate into fewer or less pronounced drug-drug interactions.
Brecanavir exhibits a resilient resistance profile due to an adaptive thiazolylmethyl moiety. To look at this property closer, investigators in a study1 that was presented at the XVI International AIDS Conference looked at the cross-resistance profile of brecanavir in 105 isolates with previously documented PRO resistance. The first set of 55 isolates was obtained from Monogram Biosciences, Inc., and was described as containing "worst case" viruses based on the presence of PRO mutations at codons 10, 32, 46, 47, 50, 54, 84 and/or 90 (major + minor mutation: mean = 11, range seven to 18). The second set of 50 isolates included viruses selected based on the presence of single, double, triple and multiple protease resistance-associated amino acid substitutions (RASs), including mutations at residues 32, 33, 46, 47, 50 (V and L), 54, 82, 84 and 90 (median of six, major: two; minor: four). The isolates were then analyzed for IC50 and fold change (FC) versus all approved PIs (except nelfinavir [NFV, Viracept]) using a PhenoSense assay.
The study found that the mean number of major PI RASs per isolate was 2.6 (range: zero to six; median three). The median IC50 for each of the other PIs was significantly above that for brecanavir.
Brecanavir showed greater potency than amprenavir (APV, Agenerase), indinavir (IDV, Crixivan), lopinavir (LPV), atazanavir (ATV, Reyataz) and tipranavir and had a lower FC than all PIs except tipranavir + ritonavir, which shows relatively low intrinsic potency and has a low clinical cut-off.
The resistance profile and the activity of brecanavir against resistant isolates support the further development of this agent. This, coupled with the low dose needed for activity, the low expected drug interaction profile and the great tolerability seen on phase 2a studies, makes this candidate an exciting agent that we should be hearing more about at future conferences as it moves along the development pipeline.