Comprehensive Resistance Testing in Patients Who Did Not Achieve SVR

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1 Comprehensive Resistance Testing in Patients Who Did Not Achieve SVR after Treatment with Sofosbuvir (GS- 7977)-Containing Regimens in Five Phase 2 Studies ES Svarovskaia 1, H Dvory-Sobol 1, V Gontcharova 1, S Chiu 1, C Hebner 1, J Perry 1, R Hyland 1, K Kowdley 2, E Lawitz 3, E Gane 4, B Symonds 1, J McHutchison 1, MD Miller 1, and Hongmei Mo 1 1 Gilead Sciences, Foster City, CA; 2 Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA; 3 Alamo Medical Research, San Antonio, TX; 4 Auckland City Hospital, Auckland, New Zealand HCV Resistance Workshop 2013

2 Introduction Sofosbuvir (SOF, formerly GS-7977), a novel prodrug of an HCV NS5B nucleotide inhibitor, demonstrated potent antiviral activity with broad HCV genotype coverage with high sustained virologic response (SVR) rates in patients In vitro selection studies show that NS5B S282T is the primary mutation selected by SOF in GT1a, 1b, 2a, 2b, 3a, 4a, 5a and 6a replicon cells

3 Objective To evaluate the selection of the S282T NS5B resistance mutant by deep sequencing in patients from all sofosbuvir-containing treatment arms who did not achieve SVR24 To evaluate the selection of other NS5B variants at the relapse time point To evaluate any change in susceptibility to SOF and RBV

4 SOF Phase 2 Studies and Samples Analyzed by Deep Sequencing Study Treatment regimen Total Subjects Treated Subjects Qualified for Sequencing Subjects with Deep Sequencing Data P PROTON P ATOMIC P ELECTRON P wks SOF followed by 44 wks PEG+RBV SOF+PEG+RBV 12 wks GT 1/2/3 SOF+PEG+RBV 12 wks GT1/4/6 SOF, SOF+RBV, SOF+PEG+RBV 12 wks GT1/2/ Quantum P (Arm C & G) SOF+RBV GT1/2/ Total * 74 * All subjects qualified due to relapse or early discontinuation, no on-sof treatment breakthrough

5 Summary of Population and Deep Sequencing Analysis at NS5B Position 282 Across Phase 2 Studies at Relapse GT Number of Patients with Relapse Samples Sequenced Population Deep NS5B 282 Variants >1% 1a All WT S282 1b All WT S N=1 S282T All WT S282 Total All WT S282

6 Phenotypic Data for NS5B Amino Acid Changes Developed in >2 SubjectS by Population Sequencing at Relapse NS5B Variant # Subject s AA Change from BL Observed Polymorphic Site? SOF Fold Change from Baseline RBV Fold Change from Baseline 11I 4 V11I, V/I11I, V11V/I Polymorphic N 5 S/N62N, S62S/N Polymorphic S 130N 206K 5 N/S110S Polymorphic S130S/N, T130N, T/N130N Q/K206K, Q206Q/K/R Polymorphic Polymorphic Q 4 R/Q300Q, R300R/Q Polymorphic

7 Structural Location of NS5B Substitutions Observed in >2 Subjects Thumb SOF 110S 206K 300Q Fingers Palm 62N 11I 130N

8 Susceptibility of Relapse Patient Isolates to SOF N=64 Significant EC 50 /EC 90 fold-change from reference (FCRF) or baseline (FCBL) only observed from SOF monotherapy subject with detectable S282T at relapse (a)

9 Clonal Phenotyping of S282T Relapse Patient Sample Population Sequence Change From BL: NS5B Replication Capacity (%) SOF Fold Change from Baseline SOF Fold Change from Reference Clone #1 Clone #1 Revertant Clone #2 T53T/P, V67A/V, S79N, V/I147I, S282T, T/I309T, T/I/A/V312T, V405A/V T53T/P, V67A/V, S79N, V/I147I, T/I309T, T/I/A/V312T, V405A/V S79N, V/I147I, S282T, T/I309T, T/I/A/V312T 1.4 ± ± ± Clone #2 Revertant S79N, V/I147I, T/I309T, T/I/A/V312T 9.6 ± Clone #3 Clone #3 Revertant S79N, V/I147I, S282T, T/I309T, T/I/A/V312T, T438A/T S79N, V/I147I, T/I309T, T/I/A/V312T, T438A/T 1.9 ± ± Susceptibility to SOF restored when S282T patient clones reverted to S282S

10 Population and Deep Sequencing Results for the Genotype 2b Subject with Detectable S282T after SOF Monotherapy Visit (confirmation) Follow-up week 8 Population Sequence Change From BL: NS5B S79N V/I147I S282T I/T309T T/A/I/V312T S79N V/I147I S282T I/T309T T/A/I/V312T S79N V/I147I S282S/T I/T309T T/A/I/V312T Deep Sequencing: S282T 1% >99% S282T 97.3% S282T 27.6% S282T Follow-up week 12 S79N V/I147I I/T309T T/A/I/V312T >99% WT S282 Follow-up week 24 S79N V/I147I I/T309T T/A/I/V312T >99% WT S282 8 S79N V/I147I I/T309T T/A/I/V312T >99% WT S282

11 HCV RNA Kinetics in the Subject Who Developed S282T at Relapse after SOF Monotherapy AGC 43% AGT 57% S282S ACT 0.05% S282T HCV RNA (IU/mL) BL sample AGC 43% AGT 57% ACT 97% S282T AGT 2.4% S282S ACT 99% S282T ACT 0.5% S282T AGT 91% TCT 7.2% ACT 27% S282T AGT 68% TCT 4% S282S S282S AGT 60% TCT 40% S282S 2 LOD=15 IU/mL 1 0 SOF Weeks Follow-up sample S282S ACT 0.1% S282T Relapse sample ACT (S282T) reversion TCT (S282S) AGT (S282S)

12 Population and Deep sequencing for Week 24 and 48 post-sof samples Deep seq: A G T (S282S, WT, 59.4%) T C T (S282S, WT, 40.2%) Pop seq Interpretation: Y R T A G T (S282S, WT) T C T (S282S, WT) A C T (S282T) T G T (S282C) S282C/S/T The detection of S282T/C was due to limitation of population sequencing

13 Conclusions Sofosbuvir (GS-7977) has a high HCV resistance barrier from pooled phase 2 analyses No virologic breakthrough on therapy Among relapsers, S282T resistance mutation not detected by deep sequencing in any patient following SOF + RBV +/- PEG treatment and detected in only 1 patient after SOF monotherapy No other NS5B genotypic or phenotypic resistance to SOF identified S282T had reduced fitness in patient and decreased replication capacity in vitro These results support the use of SOF-containing regimens for the initial treatment of HCV and possibly as a retreatment option among relapse patients.

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