4/30/2015

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AU Edited: 04-27-2015

David L. Wyles, MDAssociate Professor of Medicine

University of California San DiegoLa Jolla, California

Interactive Case-Based Presentations

and Audience Discussion

Los Angeles, CA: April 28, 2015 (ADVANCED)

Slide 2 of 50

Considerations in patients failing a DAA-based regimen

• Was interferon part of the regimen–What was the specific response?–Dose reductions on treatment?

• What specific medication classes were used–What role dose resistance play?

• Stage of liver disease• Indications of other problems

–Adherence?– Significant drug interactions?– Immunosuppression?

Slide 3 of 50

Case 1

57 yo male with DM and HCV GT1a, F3/4 on biopsy treated with PEG/RBV/TVR in 2011.

Treatment complicated by severe anemia and neutropenia

– Week 8: Required transfusion, RBV dose reduction

– Week 12: PEG dose reduction, GCSF

– HCV RNA 127 IU/ml at week 4; viral BT at week 26

• Treatment discontinued– Current HCV RNA 2.7 million

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Slide 6 of 50

HCV and HIV replication dynamics

Long-lived Reservoir

t1/2≈ 0.7 d

~ 2.0 d

<1%

>99%

t1/2≈ wks* t1/2 > 44 mo

~97%

t1/2≈ 10 hrs

~ 7.0 d*

Perelson A Science 1986. Markowitz M J Virol 2003. Finzi D Nat Med 1999. Neumann A, Science 1999. Guo J. J Virol 2003.

t1/2≈ 1 hrt1/2≈ 0.75 hr

Extra-hepatic

Reservoir

~3%

t1/2 ≈ 2.6 d

Slide 7 of 50

Virus characteristics and resistance potential

HCV10

12 virions/day

Error prone viral polymerase (x2)

No overlapping reading frames

Moderate infected cell turnover

Dynamic replication unit

Cytoplasmic replication(t1/2 ~10hrs)

No latent reservoir

Cure possible

HIV10

10 virions/day

Error prone viral polymerase

Overlapping reading frames

Rapid infected cell turnover (t1/2 ~24hrs)

Static replication unit

Integrated proviral DNA

Latently infected Tcells

Control, not cure

Viral Quasispecies

Slide 8 of 50

Resistance potential and HCV antiviral classes

ClassAntiviral Potency

GenotypeActivity

Mutational Barrier

FitnessResistance

barrier

Proteaseinhibitors

+++ to ++++ 1 (and 4) 1a<1b Variable

Low to moderate

NS5B Nucleoside/tide

++++ 1-6 -- Very low Very High

NS5BNon-nucleoside

++ to +++ 1 variable High Very low

NS5A inhibitors

++++ 1, 4-6(+/- 2,3)

1a<1b Moderate-High

Low

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Slide 9 of 50

Cross-resistance among HCV PIs

Telaprevir Boceprevir Simeprevir Asunaprevir ABT-450/r

V36A/M

T54A/S

V55A

Q80K

R155K

A156S

A156T,V

D168A/V/E

V170A/T

Slide 10 of 50

0.6

Pro

bab

ility

Time after failure (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18

median

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ility

0 2 4 6 8 10 12 14 16 18

Time after treatment failure (months)

median

Decay of resistant variants

• Follow-up of all non-SVR subjects in phase 3 trials with Telaprevir

Time

(months)

Probability

0 26%

3 36%

6 48%

12 71%

16 96%

Probability of being WT 1

1 Based on Kaplan-Meier estimation using population sequencing; hash marks in plot

indicate censored observations

Sullivan JM et al. J Hepatol. 54: S4, 2011.

Slide 11 of 50

Loss varies by resistant variant

Pro

bab

ility

Time After Treatment Failure (months)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 2 4 6 8 10 12 14 16 18

R155K

V36M

A156S/T

V36A

T54A

Common 1a variants

Common 1b variants

median

Sullivan JM et al. J Hepatol. 54: S4, 2011.

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Slide 12 of 50

Similar pattern with decay of SMV resistant variants

Lenz O. EASL 2014.

91% of nonSVR with resistance1a: R155K +/- Q80K

1b: D168V

Slide 13 of 50

Case 1 continuedPatient returns in January 2015 requesting treatment with the “new drugs”. No acute events but has felt more fatigued. Updated labs show:

• ALB 3.8, AST 57/ALT 49, TB 0.9 DB 0.4 INR 1.2

• PLT 115, Hgb 13.5 g/dL

• US (11/2014) Nodular liver without focal lesions. PV 15mm, splenomegaly, no ascites

Slide 14 of 50

Review from Dr. Peters’ discussion

1. Does this patient need a repeat biopsy?

2. What other testing is indicated for this patient?

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Slide 16 of 50

• Treatment experienced

– 52% HCV PI failures

– 44% null responder

• 20% cirrhosis

All relapses were in 12 week arms (11; 2%)

– 82-86% SVR in cirrhotics

94 96

99 99

0

20

40

60

80

100

SVR

12 (

%)

12wk 12wk + R 24wk 24wk + R

Afdahl N. NEJM 2014.

SOF/LDV

SOF/LDV/r

SOF/LDV

SOF/LDV/r

12 24Weeks

N=109

N=111

N=109

N=111

ION

-2

Nucleotide plus NS5A for treatment experienced GT1: ION-2

Slide 17 of 50

SOF + LDV: Responses in PI treated subjects

12 + R12 24 + R24

94 97 99 100

0

20

40

60

80

100

12wk 12wk + R 24wk 24wk + R

SVR

12 (

%)

66 64 50 51

ION-2 Afdahl N. NEJM 2014.

Slide 18 of 50

SOF + LDV ± RBV

• Double-blind study

• Treatment experienced cirrhotic patients– All failed both Peg/RBV then P/R/PI

– Groups were well matched• Plt <100k: 18% vs 17%

• ALB <3.5: 8% vs. 17%

SIRIUS Bourliere M. #LB-6 AASLD 2014.

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Slide 19 of 50

SOF + LDV ± RBV: 12 vs 24 Wks

SIRIUS Bourliere M. #LB-6 AASLD 2014. Bourliere M. #82 AASLD 2014

Slide 20 of 50

Real World Data: Impact of prior PI therapy?

Dieterich D. #46 AASLD 2014. Jensen D. #45 AASLD 2014.

8185

79

0

8992

87

75

0

20

40

60

80

100

All NC Cirr DC

SVR

4 (%

)

PI failure No PI

No data on Q80K; vast majority did not have it tested.97% concordance between SVR4 and SVR12.

TARGET

80 82

0

20

40

60

80

100

SVR12

SVR

12 (

%)

PI failure No PI

Slide 22 of 50

SOF Resistance• AASLD 2013: No S282T in 4 phase 3 studies

– Studies across GTs 1-4 (NEUTRINO, FISSION, FUSION, POSITRON)

– 226 non-SVRs: 221 UDS (1% detection level)

• No S282T identified

– 1/294 non-SVRs with S282T (Svarovskaia E. CID 2014)

• AASLD 2014: No S282T in phase 3 SOF/LDV

– L159F +/- V321A seen as TEVs

– 15% L159F with SOF; 1% with SOF/LDV

– impact on response?

• 1.6% at baseline w/ L159F: 100% SVR in SOF/LDV (23/23)

Svarovskaia E. AASLD 2013. Gane E. #43 AASLD 2014.

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Evolution of sofosbuvir resistance in the subject with S282T.

Svarovskaia E S et al. Clin Infect Dis. 2014;59:1666-1674

© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases

Society of America. All rights reserved. For Permissions, please e-mail:

journals.permissions@oup.com.

Slide 25 of 50

Retreatment of SOF failure with SOF/LDV + RBV: GS-US-342-1118

Wk 0 Wk 12 Wk 36Wk 24

LDV/SOF + RBV SVR12SOF failures

(n=51)

LDV/SOF SVR12LDV/SOF failures

LDV/SOF + RBV SVR12SOF failures (advanced liver disease)

Wyles D. AASLD 2014.

Slide 26 of 50

Baseline CharacteristicsLDV/SOF + RBV 12 weeks

n=51

Mean age, y (range) 54 (27‒68)

Men, n (%) 31 (61)

Black/African American, n (%) 8 (16)

Hispanic/Latino, n (%) 4 (8)

Mean BMI, kg/m2 (range) 30.4 (21.1‒47.9)

IL28B non-CC, n (%) 47 (92)

GT 1a, n (%) 30 (59)

Mean HCV RNA, log10 IU/mL (range) 6.2 (4.4‒7.3)

HCV RNA ≥800,000 IU/mL, n (%) 38 (75)

Prior HCV treatment, n (%)

SOF + PEG/RBV 25 (49)

SOF ± RBV* 21 (41)

SOF placebo† 5 (10)

Cirrhosis, n (%) 15 (29)

Wyles D. AASLD 2014.

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Slide 27 of 50

24

98 100 100 98 98 98

0

20

40

60

80

100

Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12 SVR24

HC

V R

NA

<LLO

Q,

%

Error bars represent 95% CIs.EOT, end of treatment.

51/5112/51 51/51

HC

V R

NA

<LLO

Q,

%

50/5150/51 50/5150/51

On-Treatment Viral Kinetics and SVR Rates

Wyles D. AASLD 2014.

14/14 SOF/RBV failures achieved SVR12 with SOF/LDV for 12 weeks.Osinusi A. EASL 2014.

Slide 28 of 50

Case 262 WM with cirrhosis who was treated in the ION-2 study. Received 12 weeks of SOF/LDV (no RBV). CPT A5.

• Week 4: HCV RNA <25 IU/mL (detected)

• All subsequent HCV RNA TND

• SVR4 f/u: AST/ALT: 45/67….

–HCV RNA: 253,000 IU/mL

Slide 29 of 50

Case 2He returns to clinic to discuss treatment options. Now about 4 months post relapse.

• Updated labs:

– PLT 61, Hgb 13.8 g/dL

– AST/ALT: 59/59, TB 0.7, DB 0.3, ALB 4.1, INR 1.0

– Cr 1.29 (prior 1.08)

– HCV RNA 1.2 million

• U/S: Nodular liver, no lesions. 12mm PV, 15cm spleen. No ascites. Non-occlusive R PVT.

• EGD: grade 1 esophageal varices

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Slide 31 of 50

NS5A Inhibitor Resistance

• Similar resistance pattern for 1st gen NS5A with respect to GT 1a and 1b

Kitrinos KM. #1949 AASLD 2014. Wang C. AAC 2013

Slide 32 of 50

Not all NS5A inhibitors are created equalEC50 (pM) 1a 2a 3 4 6

LDV 34 21000 35000 110 120

DCV 50 71 150 12 --

GS-5816 12 9 12 9 6

Elbasvir 4 3 20 3 --

ACH-3102 26 <10x FC in EC50

ABT-530 2 2 2 2 3

Wang C. AAC 2012. Zhao Y. #A845 EASL 2012. Ng T. #639 CROI 2014.

Later generation compounds retain activity against variants at polymorphic site (Q30, L31) and those associated with resistance (28, 30, 31, 58, and 93).

16% (12/76)Patients with NS5ARAVs

84% (64/76) Patients without NS5A RAVs

Before LDV Treatment

At Virologic Failure

99% (72/73)

Patients with NS5A RAVs

NS5A RAVs in Patients Treated With LDV Regimens Without SOF

Wyles D. EASL 2015.

4/30/2015

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Parent Study

Durability of treatment emergent RAVs

98 100 98 10095

86

0

20

40

60

80

100

VF Baseline FU-12 FU-24 FU-48 FU-96

Pati

ents

Wit

h N

S5A

RA

Vs

(%)

Registry Study

62/63 58/58 42/43 45/45 52/55 50/58

NS5A RAVs persisted in majority of patients for 96 weeksWyles D. EASL 2015.

14%

19%

33%

34%

16%

22%62%

Number of NS5A RAVs at Baseline and Follow-Up

Baseline Registry Follow-Up Week 96

No RAVs

1 RAV

2 RAVs

≥3 RAVs

Number of RAVs per patient declined over the 96-week observation period

Wyles D. EASL 2015.

Slide 36 of 50

RAV persistence after 3D treatment

NS3 NS5A NS5B

Krishnan P. EASL 2015.

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Slide 38 of 50

Baseline NS5A resistance and SOF/LDV

• Deep sequencing analysis of baseline samples (n=1904) in phase 2/3 SOF/LDV studies

– ELECTRON, LONESTAR and ION studies

Sarrazin C. #1926 AASLD 2014.

97%

93%

GT 1 (n=2137)

98%95%

GT 1b (n=529)

96%

92%

GT 1a (n=1602)

NS5A RAVsNo NS5A RAVs

SVR12 (%)

Slide 39 of 50

Baseline NS5A resistance and SOF/LDV

Sarrazin C. #1926 AASLD 2014.

<100X

>100X

No RAVs

Slide 40 of 50

We got our hopes up…based on the “infamous” SOF LDV patient.

LONESTAR Lawitz E. #215 AASLD 2013.

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Slide 41 of 50

Retreatment of SOF failure with SOF/LDV + RBV: GS-US-342-1118

Lawitz E. EASL 2015.

Wk 0 Wk 12 Wk 36Wk 24

LDV/SOF + RBV SVR12SOF failures (n=51)

LDV/SOF SVR12LDV/SOF failures(n=41)

LDV/SOF + RBV SVR12SOF failures (advanced

liver disease)

Slide 42 of 50

Retreatment of SOF failure with SOF/LDV + RBV: GS-US-342-1118

Lawitxz E. EASL 2015.

LDV/SOF 24 WeeksN=41

Mean age, y (range) 58 (35–71)

Male, n (%) 34 (83)

Black/African American, n (%) 10 (24)

IL28B non-CC, n (%) 38 (93)

GT 1a, n (%) 34 (83)

Mean HCV RNA, log10 IU/mL (range) 6.2 (4.5–7.4)

Cirrhosis, n (%) 19 (46)

Prior HCV treatment, n (%)

LDV/SOF ± RBV 33 (80)

LDV/SOF + GS-9669 8 (20)

Prior HCV treatment duration, n (%)

8 weeks 30 (73)

Presence of NS5A RAVs 19 (63)

12 weeks 11 (27)

Presence of NS5A RAVs 11 (100)

Slide 43 of 50

SVR12 with retreatment

32

95 100 100

7371

0

20

40

60

80

100

Wk 1 Wk 4 Wk 8 EOT SVR4 SVR12

Lawitz E. EASL 2015.

Retreatment of SOF failure with SOF/LDV + RBV

4/30/2015

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44

Results: SVR12 by Subgroup

68

80

100

74

46

60

0

20

40

60

80

100

No Yes 8 wks 12 wks No Yes

22/34 7/7 15/22 14/19 11/11 18/30

Cirrhosis Prior Treatment

Duration

Baseline NS5A

RAVs

All 11 patients without NS5A RAVs received 8 weeks of prior treatment

SV

R12 (

%)

Lawitz E. EASL 2015.

Retreatment of SOF failure with SOF/LDV + RBV

Results: SVR12 by Baseline NS5A RAVs

70

58

42

50

0

20

40

60

80

100

Q30 L31 Y93 Other*

9/13 7/12 2/45/12

*Other: M28T (n=2), S38F, H58D and A92T (n=1 each)

100

69

50

0

20

40

60

80

100

None 1 ≥2

11/11 11/16 7/14

Number of NS5A RAVs

SV

R12 (

%)

NS5A RAVs

(H/R/T/Y/N/K) (M/I/V) (H/N)

Lawitz E. EASL 2015.

Retreatment of SOF failure with SOF/LDV + RBV

Slide 46 of 50

The optimal re-treatment approach for this patient is unknown.

• What does the addition of RBV do?

• Triple therapy studies are being designed.

–Nuc/NS5A/PI

• Are failures of 3D + RBV any different?

• Do we need to go back to adding PEG?

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Slide 47 of 50

Conclusions• Interferon plus DAA (PI) treated

patients respond well to DAA retreatment.

• SOF failure + IFN respond similarly well

• IFN-free DAA failures do not have an established retreatment approach.

• Resistance to NS5As appear to impact re-treatment responses