Enanta Pharmaceuticals Inc (ENTA)

[willyw]

http://www.aasld.org/sites/default/files/2016-AbstractSupplement-TheLiverMeeting.pdf
(page 420)

849
Analysis of HCV Variants in the MAGELLAN-1 Part 1
Study: ABT-493 and ABT-530 Combination Therapy
of Genotype 1-Infected Patients Who Had Failed Prior
Direct Acting Antiviral-Containing Regimens

North Chicago, IL
Background: ABT-493 (NS3/4A protease inhibitor [PI] iden-
tified by AbbVie and Enanta) and ABT-530 (NS5A inhibitor) are next generation HCV direct-acting antiviral agents (DAAs).

Co-administration of ABT-493 + ABT-530 achieved a high
sustained virologic response 12 (SVR12) rate in DAA-naïve
patients with HCV genotype (GT) 1-6 infection, as well as GT1-infected patients who had previously failed a DAA-containing regimen.
.
In this report we present the characterization
of variants detected in samples from subjects enrolled in Part 1
of the MAGELLAN-1 study: treatment with ABT-493 + ABT-530
± RBV for 12 weeks in non-cirrhotic GT1-infected patients who
had previously failed regimens containing a PI and/or NS5A
inhibitor, ± an NS5B polymerase inhibitor.

Methods: Next generation sequencing (NGS) was performed on HCV NS3/4A and NS5A genes from all baseline samples and the first available sample after virologic failure with HCV RNA ≥
1000 IU/mL.

Sequencing results at 1% and 15% detection cutoffs were
examined for the presence of resistance-associated variants (RAVs) in the NS3 and NS5A genes.
Results: NGS (with 1% cutoff) of baseline samples from all patients (n=50) identified RAVs in 41 (82%) patients:
15 (30%) in NS3 only,
10 (20%) in NS5A only, and
16 (32%) in both targets
.
In 90% (37/41) of these samples, the RAVs were also present using an NGS detection cutoff of 15%. These DAA-experienced patient cohorts had broad representation of baseline variants at key resistance-associated positions, including those at NS3 V36, Q80, R155, and D168, as well as NS5A M28, Q30, L31, and Y93
.
All patients with baseline variants at position Y93 in
NS5A that confer high level of resistance to currently approved
NS5A inhibitors achieved SVR12 (n=10)
.
Of the 2 out of 50
(4%) patients who experienced virologic failure, 1 patient had
baseline NS3 (Y56H and D168A/T) and NS5A (M28V and
Q30L/R) RAVs, and the other patient had baseline RAVs in NS5A (L31M and H58D) only.

Conclusions: The combination of ABT-493 and ABT-530 demonstrated potent antiviral activity
and a high barrier to resistance in non-cirrhotic HCV GT1-in-
fected patients who had previously failed a DAA-containing regimen, regardless of the diverse profile and high prevalence of baseline NS3 and/or NS5A RAVs among these patients. These promising results support the study of this combination regimen in a larger cohort of DAA-experienced patients.