The Era of Direct-acting Antivirals Has Begun

The Beginning of the End for HCV?

Marie-Louise Vachon, M.D., M.Sc.; Douglas T. Dieterich, M.D.

Disclosures

Semin Liver Dis. 2011;31(4):399-409. 

In This Article

GS-9451 and GS-9256

GS-9451 is a potent macrocyclic HCV NS3 PI that achieved a median maximal change in HCV RNA of 3.6 log10 IU/mL (range, -4.7 log10 to -3.1 log10 IU/mL) following 3-day monotherapy in treatment-naïve patients with HCV genotype 1 infection during phase I.[28] It is currently being evaluated in phase II studies in combination with other DAAs. A phase IIb study with RGT will evaluate the efficacy and safety of 16 and 24 weeks of a four-drug regimen with GS-9451 and tegobuvir (a nonnucleoside HCV polymerase inhibitor) and 24 weeks of a three-drug regimen of GS-9451 without tegobuvir, all with pegIFN and RBV. Other phase II studies evaluating different DAA combinations that include the NS5A inhibitor GS-5885 are ongoing.

GS-9451 has additive to synergistic antiviral activity when combined with pegIFN, RBV, NS5A inhibitors, or polymerase inhibitors. Although a PI, GS-9451 retains activity against V36M and T54S, two NS3 mutations. However, R155K, A156T, and D168V are cross-resistant to GS-9451. The NS3 resistance mutations selected during treatment with GS-9451 are fully susceptible to other HCV inhibitor classes.[29] This supports its use in combination with other DAAs of the company's pipeline. A new study evaluating a four all-oral drug regimen is currently recruiting patients. In this study, GS-9451 is administered with GS-5885 (a NS5A inhibitor given at two different dosages), tegobuvir, and RBV for 12 or 24 weeks in patients with chronic HCV genotype 1 infection. This type of combination could completely revolutionize HCV treatment if found potent and well tolerated.

GS-9256 is also a potent PI that was being evaluated until recently. Preliminary results of the phase II study evaluating GS-9256 in combination with tegobuvir ± RBV and ± pegIFN for 28 days have been presented.[28] With the three oral drugs, 38% achieved RVR, 100% then achieved complete early virologic response (cEVR; undetectable HCV RNA at week 12) and maintained undetectability at week 24. With four drugs, 100% achieved RVR and were still undetectable at week 24. Without RBV and pegIFN, GS-9256 and tegobuvir led to RVR in only 7% of patients (1/15). Of these 15 patients, 12 achieved cEVR following the addition of pegIFN/RBV. All combinations were well tolerated. It was decided that GS-9256 would not be further developed, in part due to its higher potential to inhibit the transport and metabolism of bilirubin compared with GS-9451.[30]

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