genotype 3: the exception to all the...

Genotype 3: The exception to all the rules !

Douglas T. Dieterich, M.D

Director, Institute for Liver Medicine

Professor of MedicineDivision of Liver Diseases,

Icahn School of Medicine at Mount Sinai

Genotype Distribution of Hepatitis C

2

GT1a36%

GT1b24%

GT1 (Others)a

10%

GT216%

GT312%

GT41%

GT50.03%

GT61%

• HCV GT3 is the second most common genotype worldwide, estimated to affect 54.3 million people globally1

• In the US, 12% of chronic HCV patients are GT3, the third largest population2

aSubjects with genotype 1 and undetermined subtype. GT=genotype.1. Messina JP, et al. Hepatology. 2015;61:77-87. 2. Manos MM, et al. J Med Virol. 2012;84:1744-1750.

HCV GT3 Infection Has a Unique Pathophysiology Compared to Other Genotypes

3

Burden of

disease

Accelerated

fibrosis1

Steatosis, as

compared to

HCV GT11

Increased risk

for HCC2

Lower

response to

available

therapies1

Higher risk

for late-stage

liver events

compared to

HCV GT13

Higher

mortality

compared to

HCV GT13

HCC=hepatocellular carcinoma.1. Tapper EB, Afdhal NH. J Viral Hepat. 2013;20:669-677. 2. Nkontchou G, et al. J Viral Hepat. 2011;18:e516-e522. 3. McCombs J, et al. JAMA Intern Med. 2014;174:204-212.

HCV GT3 Infection Is Linked to Hepatic Steatosis

Metabolic Steatosis1-3

• Associated with high BMI, hyperlipidemia, and insulin resistance

• HCV acts as a cofactor in the development of the metabolic type of steatosis– HCV induces insulin resistance,

inducing the development of hepatic steatosis

Virally Induced Steatosis1,4

• Directly triggered by the cytopathic effect virus

• Virally induced steatosis is predominantly, and perhaps strictly, linked with HCV GT3 infection– In case of HCV GT3, a direct

relation between intrahepatic viral load and steatosis is observed, suggesting a direct viral effect

4

Across two studies, successful HCV treatment significantly improved or resolved hepatic steatosis in subjects infected with HCV GT3, but not in

those infected with GT11,5-7

BMI=body mass index.1. Roingeard P. J Viral Hepatitis, 2013;20:77-84. 2. Vanni E et al. Hepatol. 2009;50:697-706. 3. Milner KL et al. Gastroenterology 2010;138:932-941. 4. Rubbia-Brandt L, et al. J Hepatol. 2000;33:106-105. 5. Tapper EB, Afdhal NH. J Viral Hepatitis. 2013;20:669-677. 6. Kumar D, et al. Hepatol 2002;36:1266-1272. 7. Caśtera L, et al. Gut. 2000;53:420-424.

Pathogenesis of Hepatic Steatosis in Chronic HCV GT31-3

51. Roingeard P. J Viral Hepatitis. 2013;20:77-84. 2. Syed GH, et al. Trends Endocrinol Metab. 2010;21:33-40. 3. Asselah T, et al. Gut.2006;55:123-130.

• GT3 infection leads to alteration of lipid homeostasis in the liver cells, resulting in accumulation of lipid droplets and hepatic steatosis1,2

Increase Decrease

HCV GT3 Infection Associated With Higher Risk of Liver Disease Progression Compared to GT1

Nearly 1 of every 8 patients with chronic HCV in the US has GT31

Progression to Fibrosis Stage F3–F4*,†,2

• GT3 was associated with maximum likelihood of accelerated fibrosis progression compared to GT1 or GT42

*Predictors of fibrosis progression were assessed in 1189 patients from 2000 to 2008 in the Swiss Hepatitis C Cohort Study.†As modeled by Markov maximum likelihood estimation.‡Retrospective cohort study from fiscal years 2000 to 2009 of 110,484 US veterans with HCV in 128 Veterans Affairs facilities.

1. Manos MM, et al. J Med Virol. 2012;84(11):1744-1750.2. Bochud PY, et al. J Hepatol. 2009;51(4):655-666.3. Kanwal F, et al. Hepatology. 2014;60(1):98-105.

Cirrhosis at Time of Diagnosis by

Genotype‡,3

• Risk of cirrhosis was 31% greater for GT3 patients than for GT13

6

Association of Genotype With Incidence of HCC

• Retrospective cohort study from 2000 to 2009 of 110,484 US veterans with HCV in 128 VA facilities

• Risk of HCC was 80% greater with GT3 than GT1 (adjusted HR, 1.80; 95% CI, 1.61-2.03)

7aPatients with prevalent cirrhosis and HCC were excluded from calculations of cumulative incidence.Kanwal F, et al. Hepatology. 2014;60:98-105.

Cumulative Incidence of HCC by Genotypea

0

0.80

Pro

po

rtio

n F

ree

of

HC

C

1 2 3 4 5 6 7 8 9 10 11

0.82

0.84

0.86

0.88

0.90

0.92

0.94

0.96

0.98

1.00

Number at risk 110,322 97,721 85,335 73,340 60,751 46,489 32,463 19,144 8413 1013

GT1GT2GT3GT4

Years From First Positive HCV RNA

Patient Hx

• 56 year old successful graphic artist born in UK

• Routine life insurance physical after he marries and has child in NYC.

• HCV Genotype 3a

• HCV RNA 3.2million

• HBsAb+

• Hepatitis A IgG +

• Does not want to take IFN

Treatment

• Enrolled in VALENCE clinical trial of SOF/ RBV for 24 weeks

• Perfect patient

• Showed up for all study visits

• EOT viral load negative

Question 1

• What are his chances of relapse?

– 10%

– 15%

– 20%

– 35%

Response of HCV GT3 to PegIFN/RBV

7470

57

75

8781

0

10

20

30

40

50

60

70

80

90

100

Pati

en

ts A

ch

ievin

g S

VR

(%

)

Shoeb D, et al. Eur J Gastroenterol Hepatol 2011;23:747–753.

Patient Subgroup (n=639) treated with PegIFN/RBV

S Asiann=317

Non-Asiann=322

>40 yearsn=437

<40 yearsn=201

Cirrhosisn=161

No cirrhosis n=436

Graham Foster, FRCP, PhD

8882

77

9487

62

100

89

73

95 948689

94

69

0

20

40

60

80

100

Treatment-naïve Treatment-experiencednon-cirrhotic

Treatment-experiencedcirrhotic

SOF + RBV 24 weeks (BOSON) SOF + RBV 24 weeks (VALENCE)

LDV/SOF + RBV 12 weeks (ELECTRON-2) SOF + PEG-IFN + RBV 12 weeks (BOSON)

Zeuzem S, et al. N Engl J Med 2014;370:1993–2001; Gane E, et al. EASL 2014; Oral #6; Gane E, et al. N Engl J Med

2013;368:34–44; Lawitz E, et al. Lancet Infect Dis 2013;13:401–8; Gane E, et al. AASLD 2014; Poster #LB-11; Foster GR, et al.

EASL 2015; Oral #L05; Nelson DR, et al. Hepatology 2015;61:1127–35.

OMV/PTV/RTV + DSV [package insert]; LDV/SOF [package insert]; AASLD/IDSA/IAS-USA. Recommendations for testing, managing, and treating hepatitis C;

DCV [package insert]; RBV [package insert]; AASLD/IDSA. HCV guidelines; Roth D, et al. Lancet 2015 (C-SURFER Study).

Efficacy of DAAs in HCV GT 3:SOF-based Regimens

Graham Foster, FRCP, PhD

9397 100

91 8885

94 9287

60

0

20

40

60

80

100

Overall Nonchirrotic Cirrhotic Nonchirrotic Cirrhotic

SVR

12

(%

)

Genotype 2 (12 weeks)

Genotype 3 (24 weeks)

VALENCE: Sofosbuvir + RBV for 24 weeks

Zeuzem S, et al. NEJM 2014;370:1993

Treatment-Naive Treatment-Experienced

n=73 n=250 n=30 n=92 n=2 n=13 n=33 n=100 n=8 n=45

Algahtani: Results• Genotype 3 treatment with SOF/RBV

was less effective in “real world”– TE cirrhosis -- only 44% SVR– Markers of advanced liver disease

(MELD, albumin, plt count) predictive of EVR

Alqahtani S, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0840.

0

20

40

60

80

100

16/18G3

SOF/P/R

87/133G3

SOF/R

19/22G4

SOF/P/R

3/7G4

SOF/R

12/12G4

SOF/SMV

4/4G4

SOF/SMV/R

89 86

65

43

100 10022/50

CirrExper

17/23Cirr

Naïve

18/23Non-cirr

Exper

30/37Non-cirr

Naïve

44

7874

81

26/50Cirr

Exper

4/23Cirr

Naïve

4/23Non-cirr

Exper

6/37Non-cirr

Naïve

52

1717 16

Efficacy of SOF + RBV in GT 3 patients from real-world cohorts

1. Zeuzem S, et al. N Engl J Med 2014;370:1993–2001; 2. Kowdley KV, et al. EASL 2015; Poster #P0867; 3. Welzel T, et al. AASLD 2015; Poster #1057

85

70 67

0

20

40

60

80

100

GT 3: SOF + RBV 24 weeks

Phase 3

study1

TRIO

Cohort2HCV-

TARGET3

213/250 67/96

SV

R12 (

%)

86 87

62

44

0

20

40

60

80

100

TN TE TN TES

VR

12 (

%)

No cirrhosis Cirrhosis

31/36 20/23 16/36 20/45

HCV-

TARGET3

Cirrhosis: 24% 30% 55%TE: 58% 39% 52%

87/130

PB

• Higher proportion of cirrhotics in real-world data sets may explain difference in SVR with clinical studies

RW37

8681

89 88 8981

0

20

40

60

80

100

Efficacy of other SOF-based regimens in GT 3 patients from real-world cohorts

9386

0

20

40

60

80

100

SOF + DCV for 12 weeks is not approved by the EMA for use in GT 3 patients with cirrhosis; SOF + DCV + RBV for 12 or 24 weeks and SOF + DCV for 24 weeks are not

approved by the EMA for use in GT 3 patients without cirrhosis.

1. Foster G et al. Gastroenterology 2015;149:1462–70; 2. Welzel T, et al. AASLD 2015; Poster #1057; 3. Nelson DR, et al. Hepatology 2015;61:1127–35; 4. Welzel T, et al; AASLD 2015; Oral #37; 5. Hèzode C, et al. AASLD 2015; Oral #206

Phase 3

study1

HCV-

TARGET2

SV

R12 (

%)

GT 3: SOF + PEG-IFN + RBV

12 weeks

GT 3: SOF + DCV for 12 weeks

GT 3: SOF + DCV ± RBV 24 weeks

SV

R12 (

%)

168/181

12/14

Phase 3

study3

European4 French5

Compassionate use programmes

135/152

42/49

29/33

47/58

147/166

43/53

PB

Cirrhosis: 44% 71% Cirrhosis: 21% 87% 79%

SOF + DCV 12 weeks 24 weeks + RBV 24 weeks

RW38

Treatment Course

• He relapses at SVR 4 with viral load of 4.6 million

• Very disappointed since he did everything that was asked of him

Question 2

• What do you tell him?

– Go back to the UK; Graham Foster will give you SOF Peg RBV! Suck it up!

– You cant cure them all!

– Better things are on the horizon remain hopeful!

• Its now August 2015 and he comes in asking about new treatments for HCV

Question 3

• Which combination would likely work and be available?

– SOF PEG RBV

– SOF LDV RBV

– SOF DCV

High Overall Virologic Response in HCV GT3 Patients in ALLY 31,2

• SVR12 rates comparable regardless of age, gender, baseline HCV RNA level, or IL28B allele status1,2

• Cirrhotic population: 19% in treatment-naïve group, 25% in treatment-experienced group2

− Among patients with cirrhosis, 34% (11/32) had baseline platelet counts ≤100 X 109 cells/L

• 16 patients relapsed after end of treatment and 1 patient was an on-treatment failure with detectable HCV RNA at final on-treatment visit; of these 17 patients, 12 were cirrhotic2

1. (daclatasvir) Prescribing Information. Bristol-Myers Squibb Company, Princeton, NJ. 2. Nelson DR, et al. Hepatology. 2015;61(4):1127-1135.

* HCV RNA < lower limit of quantification (25 IU/mL). †In the treatment-experienced cohort, 7 patients were sofosbuvir + ribavirin failures, of whom 5 achieved SVR12.

2 ‡Includes 11 patients with missing or inconclusive cirrhosis status.

96

63

0

20

40

60

80

1009086

89

0

20

40

60

80

100

SV

R1

2(%

)*

91/101 44/51 135/152

CirrhoticNoncirrhotic‡

115/120 20/32

Treatment-Naïve

Treatment-Experienced†

Overall

SV

R1

2(%

)*

21

ALLY-3 Study: Impact of Baseline NS5A Y93H Mutation on SVR12 Rates With Daclatasvir + Sofosbuvir

0

20

40

60

80

100

SV

R12 (

%)

98%

13%

No Cirrhosis

67%

CirrhosisAll Patients

92%

68%

25%

No Y93H With Y93H

Genotype 3

Nelson DR, et al. Hepatology. 2015;61:1127-1135.

Population sequencing.

(n=135) (n=13) (n=107) (n=9) (n=28) (n=4)

Ongoing Real-World Study: SVR12 Rates WithRetreatment of Prior DAA Failures (Genotype 3)

• RAVs in sofosbuvir + RBV failures (n=14): 100% SVR12– No RAVs: 79%

– NS5A (A30K/S): 21%

• Retreatment regimens– Daclatasvir + sofosbuvir +

RBV for 12 (n=3) or 24 (n=10) weeks

– Ledipasvir/sofosbuvir + RBV for 24 weeks (n=1)

Vermehren J, et al. J Hepatol. 2016;64(suppl 2):S188. Abstract PS103.

0

20

40

60

80

100

SV

R1

2 (

%)

100% 100%

12 Weeks(n=3)

Interim SVR12 Rates (ITT)

100%

24 Weeks(n=10)

24 Weeks(n=1)

DAC + SOF + RBV LDV/SOF + RBV

ALLY-3+: Cirrhosis +RBV

HC

V R

NA

< L

LOQ

TD/T

ND

(%)

Overall 12 Weeks 16 Weeks

0

10

20

30

40

50

60

70

80

90

100 87 88 86

2630

1416

1214

Treatment-ExperiencedCirrhotic Patients

0

10

20

30

40

50

60

70

80

90

100

Naive Experienced

HC

V R

NA

< L

LOQ

TD/T

ND

(%)

Treatment HistoryAll Patients

1213

3337

92 89

SVR12 (ITT) by Prior Treatment

Leroy V, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-3.

The case continues

• Insurance refuses to pay because he was only stage 2

• Do you send him out for cheeseburger and repeat fibroscan?

• Multiple class action lawsuits are initiated so there is hope in the future for treatment

• Do you tell him that new combinations are coming that work well for Geno 3 patients who failed a SOF based regimen?

ASTRAL-3: SVR12 By Treatment Arm

Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.

95

80

0

20

40

60

80

100

SOF/VEL SOF+RBV

SVR

12

(%

)

264/277 221/275

P=0.001

ASTRAL-3: SVR12 By Cirrhosis Status and Treatment History

Mangia A, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 249.

97 91 97 9087

66

86

63

0

20

40

60

80

100

No Yes Naïve Experienced

SVR

12

(%

)

Cirrhosis Status Treatment History

SOF/VEL SOF+RBV

163187

7380

5583

200206

176204

6471

4571

4 relapses2 other

16 relapses8 other

4 relapses2 other

15 relapses13 other

22 relapses6 other

7 relapses 7 relapses 1 non-response23 relapses2 other

191197

Background

• Sofosbuvir (SOF)1,2

– Potent antiviral activity against HCV GT 1–6

• Velpatasvir (GS-5816; VEL)3-5

– Picomolar potency against HCV GT 1–6

– 2nd-generation NS5A inhibitor with improved resistance profile

• GS-98576,7

– HCV NS3/4A protease inhibitor with potent antiviral activity against HCV GT 1–6

– Improved resistance profile compared with other HCV protease inhibitors

• SOF/VEL + GS-9857

– SOF/VEL FDC (400/100 mg) tablet plus GS-9857 100-mg tablet is taken orally, once daily

FDC, fixed-dose combination1. Jacobson IM, et al. N Engl J Med 2013;368:1867-77; 2. Lawitz E, et al. N Engl J Med 2013;368:1878-87; 3. Cheng G, et al. EASL 2013, poster 1191; 4. German P, et al. EASL 2013, poster 1195; 5. Lawitz E, et al. J Viral Hepat 2015;22:1011-9; 6. Taylor JG, et al. EASL 2015, poster 899; 7. Kirby B, et al. EASL 2015, poster 861.

28

SOF

Nucleotide

polymerase

inhibitor

VEL

NS5A

inhibitor

+

GS-9857NS3/4A

Protease Inhibitor

VELSOF

GT 1

GT 3

SOF/VEL + GS-9857

SOF/VEL + GS-9857

SOF/VEL + GS-9857

SOF/VEL + GS-9857

SOF/VEL + GS-9857

SOF/VEL + GS-9857

SOF/VEL + GS-9857

SOF/VEL + GS-9857

TN Cirrhosis (n=15)

TN No Cirrhosis(n=30)

TECirrhosis (n=17)

TN Cirrhosis (n=18)

TECirrhosis (n=19)

DAA-Experienced ± Cirrhosis (n=30)

PI-TE± Cirrhosis (n=28)

SOF/VEL + GS-9857: Study Design

SVR12

Gane E, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. 38.

Week 0 6 184 168 20

SOF/VEL + GS-9857: SVR12 Rates

100

8983

100

0

20

40

60

80

100

8 8 6 8

SVR

12

(%

)

SOF/VEL + GS-9857

17/17 25/28 15/18 19/19

8 WeeksTE

Cirrhosis

8 WeeksPI TE ±

Cirrhosis

6 WeeksTN

Cirrhosis

8 WeeksTE

Cirrhosis

3 relapses2 relapses1 withdrew consent

GT 1 GT 3


SOF/VEL + GS-9857: Prevalence and Impact of Baseline NS5A and NS3 RAVs

NS5A RAVs

NS3 RAVs

No BL NS3 RAVs

n=56

BL NS3 RAVs

n=25

(54/56)

96%SVR 88%

SVR

(22/25)

No BL NS5A RAVs

n=61

BL NS5A RAVs

n=20

90% SVR

(18/20)(58/61)

95%SVR


EASL 2016, Barcelona

High Efficacy of Sofosbuvir/Velpatasvir Plus GS-9857 for 12 Weeks in Treatment-Experienced

Genotype 1–6 HCV-Infected Patients, Including Those Previously Treated With Direct-Acting

Antivirals

Eric Lawitz1, Kris Kowdley2, Michael Curry3, Nancy Reau4, Mindie Nguyen5, Paul Kwo6, Ira Jacobson7, Tram T. Tran8, Ronald Nahass9, Federico Hinestrosa10, Robert Herring Jr.11, Michael Bennet12, Jenny C. Yang13, Luisa M. Stamm13, Di An13, Hadas Dvory-Sobol13, Diana M. Brainard13, John G. McHutchison13, Eugene

Schiff14, Mitchell Davis15, Kyle Etzkorn16, Raymond T. Chung17, David Pound18, Maribel Rodriguez-Torres19, K. Rajender Reddy20, Ziad Younes21, Edward J.Gane22

1Texas Liver Institute, San Antonio, Texas, USA; 2Swedish Medical, Seattle, Washington, USA; 3Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA; 4Rush University Medical Center, Chicago, Illinois, USA; 5Stanford University, Palo Alto, California, USA; 6Indiana University School of Medicine, Indianapolis, USA; 7Mount Sinai Beth Israel, New York, USA; 8Cedars

Sinai Medical Center, Los Angeles, California; 9ID Care, Hillsborough, New Jersey, USA; 10Orlando Immunology Center, Florida, USA; 11Nashville Gastrointestinal Specialists Inc., Tennessee, USA; 12Medical Associates Research Group, Inc., San Diego,

California; 13Gilead Sciences, Inc., Foster City, California; 14University of Miami, Florida, USA; 15Digestive CARE-South Florida Center of Gastroenterology, Wellington, Florida, USA; 16Borland-Groover Clinic, Jacksonville, Florida, USA; 17Massachusetts General Hospital, Boston, Massachusetts; 18Indianapolis Gastroenterology Research Foundation, Indianapolis, Indiana, USA;

19Fundación De Investigación De Diego, San Juan, Puerto Rico; 20University of Pennsylvania , Philadelphia, USA; 21Gastro One, Germantown, Tennessee, USA; 22Auckland Clinical Studies, New Zealand

SOF/VEL + GS-9857 - Study Design

• Two Phase 2, multicenter, open-label studies (US, New Zealand)

– GS-US-367-1168: G1

– GS-US-367-1169: G2, 3, 4, 5, 6

• Broad inclusion criteria

– HCV treatment experienced, including DAA experienced

• G1: NS5A inhibitor or ≥2 DAA classes

• G2–6: Peg-IFN + RBV or any DAA

– 50% with compensated cirrhosis

0 12 24

SVR12SOF/VEL + GS-9857N=128

Week

Lawitz E, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. PS008.

99 100 100 97 100

0

20

40

60

80

100

SVR12 Overall and by Genotype

• One patient relapsed at post-treatment week 8

• 58-year-old white female with G3a infection, HCV RNA 7.0 log10

IU/mL, and cirrhosis

SV

R12

(%

)

Overall G3G2 G4, 6G1

63/63127/128 9/934/3521/21

Lawitz E, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. PS008.

100 98 99 100 100 97 100

0

20

40

60

80

100

No Yes No Yes 0* 1 ≥2

No. of DAA ClassesPrior NS5A

ExperienceCirrhosis

SVR12 by Subgroup

*GT 2-6 patients who failed prior Peg-IFN+RBV regimens. 35

SV

R1

2 (

%)

67/67 92/93 27/2735/35 35/36 65/6560/61

Resistance Analysis

*Deep sequencing with 1% assay cutoff. 36

99%

SVR12

100%SVR12

51/51

99%SVR12

76/77

40% No Baseline

RAVs

(51/128)

60% Baseline RAVs

(77/128)

20%NS5A RAVs

only

15% NS3 RAVs

only

23%Multiple

class

RAVS2%

NS5B RAVs only

EASL 2016, Barcelona

Sofosbuvir/Velpatasvir in Combination With Ribavirin for 24 Weeks Is Effective

Retreatment for Patients Who Failed Prior NS5A-Containing DAA Regimens:

Results of the Retreatment Study

Edward J. Gane1, Mitchell L. Shiffman2, Kyle Etzkorn3, Giuseppe Morelli4, Catherine Stedman5, Mitchell N. Davis6, Federico Hinestrosa7,

Hadas Dvory-Sobol8, K.C. Huang8, Anu Osinusi8, John McNally8, Diana M. Brainard8, John G. McHutchison8, Alex Thompson9, Mark Sulkowski10

1Auckland Clinical Studies, Auckland, New Zealand; 2Liver Institute of Virginia, Richmond, Virginia, USA; 3Borland Groover Clinic, Jacksonville, Florida, USA; 4University of Florida, Gainesville, Florida, USA; 5Christchurch Clinical Studies

Trust, Christchurch, New Zealand; 6South Florida Center of Gastroenterology, Wellington, Florida, USA; 7Orlando Immunology Center, Orlando, Florida, USA; 8Gilead Sciences, Inc., Foster City, California, USA; 9St Vincent’s Hospital,

Melbourne, Australia; 10Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

9197 91

76

0

20

40

60

80

100

3334

1317

1314

Total GT 1 GT 2 GT 3

Results: SVR12 by Genotype

38

SVR

12

(%

)

1 relapse*

1 nonresponse2 relapses1 WC1 relapse+

5965

+ Relapse after discontinuing treatment at week 3 *Relapse after discontinuing treatment at Week 8, Error bars represent 95% confidence intervals; WC, withdrew consent.

SVR12 by NS5A RAVs

• 11/13 GT 3 patients with RAVs had Y93H; 9 (82%) achieved SVR12

• 5 patients had 2 NS5A RAVs; all 5 achieved SVR12

• 3 patients had NS3 RAVs; all 3 achieved SVR12

1% deep sequencing cut-off. *1 patient could not be sequenced; 1 patients who withdrew consent was excluded.

39

GT 2 (n=13*)GT 1 (n=34) GT 3 (n=16)

100% SVR

100% SVR

100% SVR

38%No RAVs

5/13

62%RAVs8/13

82%No RAVs

28/34

18%RAVs6/34

19%No RAVs3/16

81%RAVs13/16

100% SVR

77% SVR

10/133/38/85/56/6

96% SVR

27/28

ABT-493 identified by AbbVie and Enanta.1. Ng TI, et al. Abstract 636. CROI, 2014. 2. Ng TI, et al. Abstract 639. CROI, 2014.

Next Generation Direct-acting Antivirals

ABT-530PangenotypicNS5A inhibitor

ABT-493Pangenotypic NS3/4A

protease inhibitor

In vitro:1,2

• High barrier to resistance

• Potent against common NS3 variants (eg., positions 80, 155, 168) and NS5A variants (eg., positions 28, 30, 31 and 93)

• Additive/synergistic antiviral activity

Clinical PK & metabolism:

• Once-daily oral dosing

• Minimal metabolism and primary biliary excretion

• Negligible renal excretion (<1%)

Stable HCV GT3a Replicon EC50

NS3/4A Protease Inhibitor

nM NS5A Inhibitor pM

ABT-493 1.6 ABT-530 2

Grazoprevir1 35 Elbasvir7 140

GS-98572 6.1 Velpatasvir8 20

Simeprevir3,4 472 Ledipasvir9 168,000

Paritaprevir 19 Ombitasvir 19

Asunaprevir5 1162 Daclatasvir10 530

Odalasvir 48

MK-840811 2

ABT-493 and ABT-530 Have Potent Activities Against All HCV Genotypes, Including GT3

1. Lahser F, et al. AASLD, 2014. 2. Taylor J, et al. EASL, 2015. 3. Olysio prescribing information. 4. Chase R, et al. IAPAC, 2013.5. McPhee F, et al. AAC, 2012. 6. Yang H, et al. AAC, 2014. 7. Liu R, et al. AAC doi:10.1128/AAC.01390-15 8. Cheng G, et al. EASL, 2013.9. Cheng G, et al. EASL, 2012 10. Wang C, et al. AAC, 2014.11. http://files.shareholder.com/downloads/ACHN/0x0x602481/8b28c708-13b6-420d-9325-401c57b89001/ACHN_R_D_Day_Final.pdf12. Asante-Appiah E, AASLD, 2014.

NS5A Inhibitor Fold Change in EC50 for GT3 NS5A Variants

M28T A30K Y93H

ABT-530 0.4 1.1 2.5

Ledipasvir1 NA >1000 >1000

Velpatasvir2 NA 10 – 100 >100

Daclatasvir3 46 56 - 62 2738 – 2752

Elbasvir4 NA 50 486

Ombitasvir5 423 NA 6728

MK-8408 NA NA NANA, not available

ABT-530 Retains Antiviral Activity Against Common GT3 Single-Position NS5A Variants

1. Hernandez D, et al. J Clin Virol, 2013. 2. Doehle BP, et al. EASL, 2015. 3. Wang C, et al. AAC, 2013:57:611-3.4. Gane E, et al. EASL, 2015. 5. Krishnan P, et al. AAC, 2015.

•Dose-ranging part 1 of this study with •ABT-493 300 mg + ABT-530 120 mg resulted in 97% (28/29) mITT SVR12 in treatment-naïve or -experienced patients without cirrhosis treated for 12 weeks1

Prior Results in Patients With GT3 Infection, and Objective

1. Kwo PY, et al. AASLD, 2015.

Objective: Explore whether a shorter 8-week treatment duration with ABT-493 + ABT-530 would result in a similarly high SVR rate in treatment-naive GT3-infected patients without cirrhosis

SVR

12

, % P

ati

en

ts

0

10

20

30

40

50

60

70

80

90

1008993

2829

2830

300120

200120RBV

97

20040

2528

2930

200120

ABT-493ABT-530

97

12 Weeks

•No virologic failures

•1 patient withdrew consent after treatment week 6 due to intolerance of blood draws and had an undetectable HCV RNA at the time of discontinuation

mITT SVR12 rate excludes non-virologic failures

SVR12 AnalysisSV

R12

, % P

atie

nts

0

10

20

30

40

50

60

70

80

90

10097

2829

SVR12

100

mITTSVR12

2828

ABT-493 and ABT-530 +/- RBV in G3 with Cirrhosis

• Higher rates of liver steatosis and an increased risk for hepatocellular carcinoma and fibrosis progression than other HCV genotypes

• Approximately 30% of HCV infections worldwide

• Now the most difficult-to-cure genotype, particularly in patients with cirrhosis

Current EASL recommendations for G3-infected patients with cirrhosis

SVR12

SOF + RBV for 24 weeks 79%

SOF + Peg-IFN/RBV for 12 weeks 88%

SOF + DCV + RBV for 24 weeks 85%

Kwo P, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. LB01.

Kwo P, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. LB01.

ABT-493 and ABT-530 +/- RBV in G3 with CirrhosisSVR12 by ITT Analysis

100 100

0

20

40

60

80

100

.ABT-493+ ABT-530

ABT-493+ ABT-530 + RBV

SVR

12

, % P

atie

nts

24 /24

24 / 24

C-CREST 1 and 2: Grazoprevir/MK-8408/MK-3682

• 240 patients (G1a, n = 46; G1b, n = 47; G2, n = 61; G3, n = 86)

• Treatment naïve, non-cirrhotic

Gane E, et al. 51st EASL; Barcelona, Spain; April 13-17, 2016. Abst. SAT-139.

FW = follow-up week; TW = treatment week

Study Design

G1 (n=23)G2 (n=16)G3 (n=21)

Mk-3682 (300 mg) +GZR + MK-8408

Mk-3682 (300 mg) +GZR + MK-8408

D1 TW4 TW8 FW4 FW8 FW12 FW24

Mk-3682 (450 mg) +GZR + EBR

Mk-3682 (300 mg) +GZR + EBR

SVR121st Endpoint

SVR242nd Endpoint

G1 (n=23)G2 (n=15)G3 (n=22)

G1 (n=24)G2 (n=14)G3 (n=21)

G1 (n=23)G2 (n=16)G3 (n=22)

100

69

86

100

60

86

100

71

95

8794

91

0

20

40

60

80

100

G1 G2 G3

SVR

24

(%

)

C-CREST 1 and 2: Secondary endpoint


LTFU = lost to follow up† One G1b patient receiving MK-3682 (450 mg)/GZR/MK-8408 and 1 G3 patient receiving MK-3682 (300 mg) GZR/EBR were lost to follow-up between FW12 and FW24; both had achieved SVR12.

MK-3682 (300 mg)/GZR/EBRMK-3682 (450 mg)/GZR/EBRMK-3682 (300 mg)/GZR/MK-8408MK-3682 (300 mg)/GZR/MK-8408

C-CREST 1 and 2: Grazoprevir/MK-8408/MK-3682 No Impact of Baseline RAVs on SVR


0

10

20

30

40

50

60

70

80

90

100

SVR1297%

0

10

20

30

40

50

60

70

80

90

100

SVR12100%

GT1 NS5A RAVs GT1 NS3 RAVs GT1 NS5B RAVs

0

10

20

30

40

50

60

70

80

90

100

SVR1297%

0

10

20

30

40

50

60

70

80

90

100

SVR1298%

0

10

20

30

40

50

60

70

80

90

100

SVR1299%

0

10

20

30

40

50

60

70

80

90

100

SVR1295%

Prevalence Prevalence Prevalence

No RAVsn=70(76%)

No RAVsn=38(41%)

No RAVsn=73(79%)

RAVsn=22(24%)

RAVsn=54(59%)

RAVsn=19(21%)

6870

3738

7273

2222

5354

1819

0

10

20

30

40

50

60

70

80

90

100

SVR12100%

0

10

20

30

40

50

60

70

80

90

100

SVR1285%

GT3 NS5A RAVs GT3 NS3 RAVs GT3 NS5B RAVs

0

10

20

30

40

50

60

70

80

90

100

SVR12100%

0

10

20

30

40

50

60

70

80

90

100

SVR1292%

0

10

20

30

40

50

60

70

80

90

100

SVR1293%

0

10

20

30

40

50

60

70

80

90

100

SVR12100%

Prevalence Prevalence Prevalence

No RAVsn=22(52%)

No RAVsn=4(10%)

No RAVsn=41(98%)

RAVsn=20(48%)

RAVsn=38(90%)

RAVsn=1(2%)

2222

44

3841

1720

3538

11

NGS was performed with a 15% sensitivity threshold. GT3 NS5A RAVs: any change from wild type at 10 positions (24, 28, 30, 31, 32, 38, 58, 62, 92, 93).GT3 NS3 RAVs: any change from wild type at 14 positions (36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, 175).GT3 NS5B RAVs: any change from wild type at 6 positions (159, 239, 282, 316, 320, 321).

Two Doses of Nuc (MK-3682) and 2 Different NS5A Inhibitors (Elbasvir vs. MK-8408)

Gane E, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-15.

240 treatment-naïve, non-cirrhotic patients

GZR: 100 mg once-daily; EBR: 50 mg once-daily; MK-8408: 60 mg once-daily

*SVR12 =Primary endpoint (HCV RNA <15 IU/mL at 12 weeks after end of treatment), HCV RNA determined with COBAS™ Taqman™ HCV Test, v2.0®

Methods: Study Design

GT1 (n=23)GT2 (n=16)GT3 (n=21)

GT1 (n=23)GT2 (n=15)GT3 (n=22)

GT1 (n=24)GT2 (n=14)GT3 (n=21)

GT1 (n=23)GT2 (n=16)GT3 (n=21)

GZR + EBR + MK-3682 (300 mg)

GZR + MK-8408+ MK - 3682 (300 mg)

GZR + EBR + MK-3682 (450 mg)

GZR + MK-8408+ MK - 3682 (450 mg)

SVR12*: Primary

Endpoint

D1 TW4 TW8 SVR4 SVR8 SVR12

8 Week Regimen of GZR/MK-8408/MK-3682 (450 mg)

Gane E, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-15.

*Primary efficacy: SVR12 of full analysis set (FAS). All 240 enrolled patients completed 8 weeks of treatment and reached follow-up 12 weeks after end of treatment.

100

69

90

100

60

86

100

71

9591 94 91

0

20

40

60

80

100

GT1 GT2 GT3

% S

VR

12

GZR/EBR/MK-3682 300 mg GZR/EBR/MK-3682 450 mgGZR/MK-8408/MK-3682 300 mg GZR/MK-8408/MK-3682 450 mg

2323

2323

2424

2123

1116

915

1014

1516

1921

1922

2021

2022

8 Week Regimen of GZR/MK-8408/MK-3682 (450 mg) Compared to Prior 12-Week Regimens

Gane E, et al. 66th AASLD; San Francisco, CA; November 13-17, 2015; Abst. LB-15., *Zeum et al., Ann Int Med 163:1, 2015; †Brown et al., EASL,

2015, Abst P0771; ‡Gane et al., EASL, 2015, Abst P0776

95

80

45

100

71

9591 94 91

0

20

40

60

80

100

GT1 GT2 GT3

% S

VR

12

12 Weeks GZR/EBR = RBV

8 Weeks GZR/MK-8408/MK-3682 (300 mg)

8 Weeks GZR/MK-8408/MK-3682 (450 mg)

273*288

2424

2123

24†

301014

1516

9‡

20

2021

2022

Conclusion

• Geno 3 responsible for about a third of global HCV

• It causes steatosis and more rapid progression to ESLD and HCC

• It has been our most difficult genotype to treat

• Better drugs for it are on the horizon!

genotype 3: the exception to all the...

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