February 11, 2003
The investigational protease inhibitor GW433908, most commonly known as "908," is the subject of several presentations in this conference. 908 is a phosphor ester pro-drug of amprenavir (APV, Agenerase) that offers several advantages over its parental compound. One of the best attributes is the flexibility of this protease inhibitor to be administered unboosted, twice a day, or boosted with ritonavir (RTV, Norvir) once or twice daily.
At the last HIV European Conference in Glasgow, data was presented on the SOLO trial, comparing boosted 908 to NFV. Later in this conference, the final results of the NEAT trial will be presented by Dr. Jeffrey Nadler, in which unboosted 908 is compared to nelfinavir . These two naive trials are part of a trio of studies that will be used by GlaxoSmithKline and Vertex Pharmaceuticals for the final 908 registration to the U.S. Food and Drug Administration (FDA). In these two trials, all subjects received 3TC (lamivudine, Epivir) and abacavir (ABC or ABV, Ziagen) as part of their regimen.
In this poster, authored by Macmanus on behalf of GlaxoSmithKline, plasma samples with detectable viral load from patients in these two studies were further investigated to determine the emergence of resistance. Considering that in these two studies the population was naive to antiretroviral therapy, the emergence of resistance to the different regimens will be very helpful to further elucidate patterns or resistance pathways.
Baseline and virologic failure plasma samples were compared using genotypic and phenotypic testing by Virologic. In addition, the incidence of pre-treatment (or transmitted resistance) was determined using a selected subset of subjects from each of these studies. This baseline resistance was found to be less than 3 percent for the RT gene and less than 1 percent for the PRO gene.
Samples from 57 subjects (30 receiving 908 and 27 receiving NFV) were analyzed from the NEAT trial. There were no significant differences between the unboosted 908 and NFV in the incidence of selection of resistance mutations. Eight samples from each arm (908 and NFV) were found to contain PRO primary or secondary treatment emergent mutations. The mutations observed in the PRO gene from the sample of subjects on unboosted 908 were the characteristic mutations seen with APV. The evolution of the mutation I54L to I50V, previously reported with APV, was also observed with unboosted 908. Mutations that were not previously associated with APV resistance were not observed.
One hundred and one samples (39 and 62 receiving 908 and NFV respectively) were also included from the SOLO trial in this analysis. But this time no samples from the boosted 908 harbored PRO mutations, in comparison with 27 samples in the NFV arm. There was also no decrease in phenotypic susceptibility. The selection of RT mutations in the 908/ritonavir arm was significantly less than in the NFV group.
In addition, from the total of 898 subjects from both trials that received ABC and 3TC, the emergence of ABC-associated mutations other than M184V (such as K65R and L74V) was less than 1 percent.
The results of this study support the observations reported by other studies conducted with boosted PIs. By improving the pharmacokinetic profile of a PI (by adding RTV), a higher drug exposure to some extends may prevent replication and provides a higher genetic barrier to the development of resistance.
The findings in this study are very encouraging because it further supports the concept that this new protease inhibitor (908) can be sequenced successfully based on its resistance profile. If we use 908 unboosted in early treatment, the potential APV-associated mutations that could emerge are easily overcome by other boosted regimens such as lopinavir/r (LPV+RTV or LPV/r, Kaletra). On the other hand, if boosted 908 is used, a failure to this regimen will not likely result in the development of a new PI mutation.
The advantages of 908 over the old APV are numerous and all welcome. Not only will the pill burden be decreased from 16 large capsules to 4 pills, but tolerability, potency and resistance add up to a list of attributes that is going to make this drug very beneficial in all patient populations. I am looking forward to the completion of these three registration studies to have this drug finally available for use by my patients.