GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1–4 Infection
A Randomized, Double-blind, Dose-ranging Phase 1 Study
M. Rodriguez-Torres; S. Glass; J. Hill; B. Freilich; D. Hassman; A. M. Di Bisceglie; J. G. Taylor; B. J. Kirby; H. Dvory-Sobol; J. C. Yang; D. An; L. M. Stamm; D. M. Brainard; S. Kim; D. Krefetz; W. Smith; T. Marbury; E. Lawitz Disclosures J Viral Hepat. 2016;23(8):614-622.
Discussion Only
In this randomized, phase 1b study, the safety, antiviral efficacy and PK of GS-9857 at doses ranging from 50 to 300 mg were assessed in patients with chronic genotype 1–4 HCV infection. GS-9857 was generally well tolerated by patients with chronic HCV infection when administered once daily for 3 days. All AEs were of mild or moderate severity, with diarrhoea and headache occurring most commonly during this study. Although increased incidence of rash, pruritus, nausea and anaemia have been commonly reported with the use of certain protease inhibitor-based regimens,[7–10] no such events were observed during this study. Grade 3 or Grade 4 laboratory abnormalities occurred in 16.9% of patients receiving GS-9857 and were not associated with GS-9857 dose or AEs. Notably, assessments of ALT, AST and alkaline phosphatase levels did not reveal any Grade 3 or Grade 4 abnormalities, indicating that GS-9857 administration was not associated with significant changes in liver function. Physical examination and ECG evaluation did not reveal clinically significant findings.Treatment with GS-9857 at doses of 100 mg or 300 mg resulted in >3 log10 IU/mL median maximal reduction in viral load from baseline across all genotypes, including genotype 3, indicating that GS-9857 exhibited potent antiviral activity in HCV-infected patients. This observation is consistent with in vitro data showing that GS-9857 has pan-genotypic activity against genotype 1 to 6 replicons, with the half-maximal effective concentration ranging from 1.5 to 6.6 nm.[5] With the exception of patients with genotype 3a infection who received GS-9857 doses of <100 mg, a rapid and consistent reduction in HCV RNA was achieved and maintained through day 10. For patients with genotype 3a infection who received GS-9857 50 mg, HCV RNA reductions occurred more slowly.
This study characterized substitutions at positions 36, 41, 43, 54, 55, 80, 122, 155, 156, 168 and 170, which have been reported to be associated with resistance to NS3/4A protease inhibitors.[11–17] Prior to the start of GS-9857 treatment, 22.4% of patients who were sequenced harboured NS3 RAVs. Treatment with GS-9857 resulted in similar mean maximal viral load reductions in patients with and without NS3 RAVs, indicating that the antiviral efficacy of GS-9857 was maintained in the presence of mutations commonly associated with resistance to treatment. The majority of patients (73.6%) who were sequenced after 3 days of GS-9857 treatment did not have emergent NS3 RAVs, and there were no emergent NS3 RAVs in patients with genotype 2 or 4 infection. A156V or A156T were the most prevalent substitutions to emerge in patients with genotype 1a or 1b infection. In vitro data indicate that GS-9857 has potent activity against the most common genotype 1 RAVs except A156T;[5] this substitution is associated with high levels of resistance (>100-fold) but low viral fitness (1.5% compared to wild-type genotype 1a replicon).[12] The overall low frequency of emergent NS3 RAVs suggests that GS-9857 has a relatively high barrier to resistance as compared with other first-generation protease inhibitors, which may be a substantial benefit in the context of retreatment of patients who have failed a prior treatment with a DAA-based regimen.
Administration of GS-9857 at doses ranging from 50 to 300 mg under fasting conditions resulted in dose-proportional increases in exposure. The median half-life across cohorts ranged from approximately 29–42 h, supporting once-daily dosing. Consistent with its long median half-life, significant accumulation of GS-9857 exposure was observed. GS-9857 plasma PK was similar among patients with genotype 1a, 1b, 2, 3 or 4 HCV infection.
Patients with cirrhosis or chronic liver disease were excluded from this preliminary investigational study. As such, the lack of significant safety concerns observed may be the result of selection for a study population less prone to AEs. Further evaluations of GS-9857 in patients with more advanced disease or additional complications will be necessary to confirm the findings of this study.
In summary, administration of multiple doses of GS-9857 was well tolerated and resulted in a robust decline of HCV RNA levels in patients with genotype 1–4 HCV infection. Notably, the potent antiviral activity of GS-9857 was preserved in the presence of commonly observed NS3 mutations associated with resistance to protease inhibitors. GS-9857 demonstrated linear PK when administered at doses ranging from 50 to 300 mg under fasting conditions. The median half-life of GS-9857 ranged from 29 to 42 h, conducive to once-daily dosing. Lastly, GS-9857 has demonstrated additive antiviral activity when evaluated in vitro in combination with sofosbuvir or velpatasvir.[5] Together, these data support the further development of once-daily GS-9857 in combination with other DAAs for the treatment of patients with chronic HCV infection.
Full Article - GS-9857 in Patients With Chronic Hepatitis C Virus Genotype 1-4 Infection
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