The non-structural-5a gene (NS5A) of the hepatitis C virus (HCV) is an interesting treatment target. It clearly plays several roles in viral replication, but scientists are not yet entirely certain what those roles may be. However, even though the precise functions of NS5A remain uncertain, one thing about the protein is not. Investigational drugs that target NS5A have profound effects on the ability of the virus to persist and thrive in the human body.
Although NS5A is clearly a potent target for drug development, it exemplifies one of the difficulties with designing treatments for HCV. The gene, like those coding for the rest of the virus, is subject to extensive genotypic variability. Even leaving aside the problem of those treatment-driven mutations that are associated with drug resistance, there are at least 11 distinct HCV genotypes. Many of those have multiple subtypes. It is therefore unsurprising, if quite frustrating, that most medications often only work effectively on one or two.
That is why the research on the broad genotypic efficacy of Gilead’s investigational, second generation NS5A inhibitor GS-5816 is so exciting. Two studies presented at the 2013 International Liver Congress (ILC2013) already have people talking about the potential reach of the drug, even though it has only recently entered human trials.
In fact, part of the buzz reflects the fact that some of the data released at the congress was from the first safety and tolerability trials of GS-5816. The news was very good. The phase I studies found that, across a wide range of doses, GS-5816 was well tolerated by patients. No participants discontinued the study. None even stopped the drug early. There were also no laboratory abnormalities or changes in the patients’ ECGs. All in all, a very promising start.
However, the real excitement about the drug is likely more of a reflection about the in vitro data presented at ILC2013. While variations in the NS5A gene generally lead to variable efficacy of inhibitors against different common HCV genotypes, the research presented by Dr. Guofeng Cheng, suggested that GS-5816 is broadly efficacious across HCV genotypes one to four and six. Furthermore it maintains its potency even in the presence of common resistance mutations.
Even more impressive, GS-5816 seems to have a significantly higher threshold for the development of resistance than the first generation inhibitors. It remains effective across a much wider range of polymorphisms than earlier drugs, and it works well at controlling viral sub-types known to be resistant to existing medications. It also appears to function synergistically with several other classes of HCV drugs, suggesting that it might be even more valuable as part of a combination therapy.
Development of GS-5816 is still in its early days, but those attending ILC2013 are clearly excited about its promise. Broad-spectrum HCV treatments are enormously useful, particularly in lower-resource areas where getting a viral genotype may be impractical. Although it may be years before NS5A inhibitors and other direct acting antivirals (DAA) become part of standard patient care, the lack of genotype specificity seen in GS-5816 has the potential to reduce at least some of the barriers to use.