EASL UPDATE Viral Hepatitis - Swedish

1

EASL UPDATE Viral Hepatitis

Kimberly Brown, MD

Chief, Division of Gastroenterology and Hepatology

Associate Medical Director Henry Ford Hospital Transplant Institute

Henry Ford Hospital, Detroit

2

Hepatitis B

3

Key CHB Disease State Studies at EASL Series of 3 Retrospective 10-Year Longitudinal Studies of >44,000 US CHB Patients

• Based on claims from national insurance databases covering commercial, Medicare, and Medicaid beneficiaries

• Evaluation period covered 7/2006 through 6/2015

• Analyses included CHB patients ≥18 years old without HDV-coinfection

• Non-CHB controls were matched to CHB patients by CHB index year, age, gender, geographic region, and race

3

Advancing Age and Comorbidities in CHB Patients: Results of 10-Year Longitudinal Analysis of a Diverse Population-Based Cohort of 44,026 CHB Patients in the United States Nguyen M, et al. EASL 2017 PS-107.

Prevalence of Osteoporosis and Bone Fracture was 2-fold Higher in CHB Compared to Non-CHB Patients and Continued to Increase in the Last Decade: Results of a United States Population-Based Cohort Study Gordon, S, et al. EASL 2017 PS-109.

Higher and Rising Prevalence and Incidence of Renal Impairment and CKD in CHB Patients Compared to Matched Non-CHB Controls in the United States: Results of a Real-World Analysis Nguyen M, et al. EASL 2017 Poster SAT-132.

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Retrospective 10-Year Analysis of Age and Comorbidities in >44,000 US CHB Patients

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• Median age increased significantly across payer types from 2006-2015 • >50% of Commercial and Medicaid CHB patients are now >50 years old

• Comorbidities increased up to 4-fold, affecting up to one-third of all CHB patients

HTN, hypertension.

Nguyen M, et al. PS-107. Presented at: EASL International Liver Congress; April 19-23, 2017; Amsterdam, The Netherlands.

Proportion of CHB Patients With Metabolic Comorbidities, 2006-2015

9%

17%

8%

18%

32%

9%

28%

43%

8% 13%

27% 21%

27%

59%

28%

41%

76%

47%

0%

20%

40%

60%

80%

Diabetes HTN Hyperlipidemia Diabetes HTN Hyperlipidemia Diabetes HTN Hyperlipidemia

Commercial Medicaid Medicare

% o

f C

HB

Pat

ien

ts 2006 2015

P<.001 Over Time

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Retrospective 10-Year Analysis of Bone Outcomes in >44,000 US CHB Patients vs Non-CHB Matched Controls

5 Gordon, S, et al. PS-109. Presented at: EASL International Liver Congress; April 19-23, 2017; Amsterdam, The Netherlands.

• The prevalence of osteoporosis and fracture in CHB patients were significantly higher than in non-CHB controls across payers and over all time periods

• Includes prevalence rates >100x and 50x higher per 1000 persons in Medicaid and Medicare, respectively

Osteoporosis/Fracture Prevalence Rate, 2006-2015

59

125 152

314

175

307

53

112 87

204

148

249

0

50

100

150

200

250

300

350

2006 2015 2006 2015 2006 2015


Pre

vale

nce

(p

er 1

00

0 p

erso

ns)

CHB Patients Non-CHB Controls

P<.05 for CHB vs controls across all payer types over all time periods

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Retrospective 10-Year Analysis of Renal Health in >44,000 US CHB Patients vs Non-CHB Matched Controls

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• Between 2006 and 2015, the percentage of CHB patients with renal impairment* increased significantly across all payers and was significantly higher than matched non-CHB controls

Percentage of Patients with Renal Impairment,* 2006-2015

Nguyen M, et al. Poster SAT-132. Presented at: EASL International Liver Congress; April 19-23, 2017; Amsterdam, The Netherlands.

Perc

enta

ge o

f Pat

ient

s

*Renal Impairment: CKD stages I-IV, unspecified CKD, end stage renal disease, chronic pyelonephritis, glomerulonephritis, nephrolithiasis, nephropathy, renal osteodystrophy, or proteinuria.

7%

11%

15%

27%

20%

48%

2% 5% 6%

14%

9%

21%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

50%

2006 2015 2006 2015 2006 2015


CHB Patients Non-CHB Controls

P<.001 for all CHB and control comparisons over time

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Background and Aim

• Tenofovir alafenamide (TAF)

• New tenofovir (TFV) prodrug; greater plasma stability than TDF1-3

• Enhances delivery of active drug (TFV-DP) to hepatocytes1-3

• Reduces circulating levels of TFV relative to TDF4,5

• Non-inferior efficacy vs TDF with improved bone and renal safety in patients with chronic HBV at Week 486,7

1. Lee WA, et al. Antimicrob Agents Chemother 2005;49:1898-1906; 2. Murakami E, et al. Antimicrob Agents Chemother 2015;59:3563-69; 3. Babusis D, et al. Mol Pharmaceutics 2013;10:459-66; 4. Agarwal K, et al. J Hepatol 2015;62:533-40; 5. Sax P, et al. Lancet 2015;385:2606-15; 6. Chan HLY et al. Lancet Gastroenterol Hepatol 2016;1:185-95; 7. Buti M et al. Lancet Gastroenterol Hepatol 2016;1:196-206.

TAF Nucleotide reverse

transcriptase

inhibitor

7

8

Study Design GS-US-320-0108 and GS-US-320-0110

• Two Phase 3, randomized, double-blind, active-controlled trials

• Study 108 (N=425): HBeAg-negative patients

• Study 110 (N=873): HBeAg-positive patients

• Key inclusion criteria (both studies)

• HBV DNA ≥20,000 IU/mL; ALT >60 U/L (males) >38 U/L (females); eGFR ≥50 mL/min

• 2:1 randomization

• Stratified by HBV DNA level and treatment status (naïve/experienced)

8

120 144

TAF 25 mg QD

TDF 300 mg QD

0 384

TAF 25 mg (open label)

48 Week 96

Primary

Endpoint

Interim

Analysis

Brunetto M et al. EASL 2017 P-042; Agarwal K et al. EASL 2017 FRI-153

9

90 91

0

20

40

60

80

100

TAF TDF

Week 96 Efficacy: Study 108 (HBeAg Negative)

• Maintained high viral suppression rates with TAF at Week 96

HB

V D

NA

<29 I

U/m

L

257/285 127/140

-0.6%*

(-7.0, +5.8)

p=0.84

VL 29 IU/mL: 2%

No virologic data†: 8%

VL 29 IU/mL: 2%


HBV DNA <29 IU/mL

*Adjusted for baseline HBV DNA level and oral antiviral treatment status strata. VL, viral load. †Due to missing data, or early discontinuation for AE/death, withdrew consent, lost to follow-up, or other reasons

Brunetto M et al. EASL 2017 P-042 9

10

73 75

0

20

40

60

80

100

TAF TDF

TAF Week 96 Efficacy: Study 110 (HBeAg Positive)

10

HBV DNA <29 IU/mL

Week 96 Efficacy: Study 110 (HBeAg Positive)

-2.2%*

(-8.3, +3.9)

p=0.47

VL 29 IU/mL: 18%

No virologic data†: 9% VL 29 IU/mL: 14%


423/581 218/292

Higher rates of HBeAg seroconversion at Week 96 in TAF arm (18% vs 12%; p=0.05)

Low HBsAg loss rates at Week 96 (TAF: 1%; TDF: 1%)

*Adjusted for baseline HBV DNA level and oral antiviral treatment status strata. VL, viral load. †Due to missing data, or early discontinuation for AE/death, withdrew consent, lost to follow-up, or other reasons

Agarwal K et al. EASL 2017 FRI-153

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Week 96 ALT Normalization: AASLD criteria

Central lab upper limit of normal (ULN): males 43 U/L, females 34 U/L (≥69 y, males 35 U/L, females 32 U/L); AASLD criteria ULN: males 30 U/L, females 19 U/L. 11

Pa

tie

nts

, %

TAF TDF

Study 108 (HBeAg Negative) Study 110 (HBeAg Positive)

• Significantly higher rates of ALT normalization with TAF by both central laboratory and AASLD criteria

p=0.035

50%

40%

p=0.003

52%

42%

Brunetto M et al. EASL 2017 P-042; Agarwal K et al. EASL 2017 FRI-153

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Bone Mineral Density Changes Through Week 96

12 p-values from analysis of variance model including treatment as a fixed effect. *p-values from mixed model repeated measures (MMRM)

TAF treatment resulted in smaller declines in hip and spine BMD compared with TDF

TAF

TDF

Spine Hip

p <0.001* P=0.80*

Fung S et al. EASL 2017 SAT-162

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Week 96: Changes in Creatinine Clearance and CKD Stage

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TAF TDF

Me

dia

n C

ha

ng

e in

eG

FR

CG,

mL

/min

(Q

1, Q

3)

† * * * * *

Week

8 24 48 72 96

* * * * * *

-2 0

-1 0

1 0

2 0

0

Patients with ≥1 CKD Stage decline, n/n (%)

TAF 25 mg n/n (%)

TDF 300 mg n/n (%)

p-value**

0 or 1 risk factors 29/619 (5) 28/282 (10) <0.01

≥2 risk factors 17/171 (10) 26/108 (24) <0.01

Smaller Renal Impact of TAF at Week 96

Safety advantages of TAF are seen at low and high risk patient groups

Chuang WL et al. EASL 2017 SAT-171

* ≤0.001; †p <0.01; ‡p <0.05; p-values for eGFRCG from 2-sided Wilcoxon rank-sum test; **Fisher’s exact test. Risk factors are age ≥50 y, female gender, and baseline comorbidities of HTN, CVD, DM and HL.

Confidential

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EASL 2017, Amsterdam

Improved Bone and Renal Safety of Switching from Tenofovir Disoproxil Fumarate (TDF) to Tenofovir Alafenamide (TAF): Preliminary Results

From 2 Phase 3 Studies in HBeAg-positive and HBeAg-negative Patients with Chronic Hepatitis B

Henry LY Chan1, Scott Fung2, Wai Kay Seto3, Edward Gane4, John F Flaherty5, Jenny C Yang5, Lanjia Lin5, Anuj Gaggar5, G Mani Subramanian5, Wan-Long Chuang6,

Kosh Agarwal7, Harry LA Janssen8,9, Maria Buti10

1The Chinese University of Hong Kong, China; 2Toronto General Hospital, Toronto, Ontario, Canada; 3Queen Mary Hospital, Hong Kong;

4Auckland Clinical Studies, Auckland, New Zealand; 5Gilead Sciences, Inc., Foster City, CA, USA; 6Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; 7King’s College Hospital, London, UK; 8Toronto Western Hospital, Toronto, Ontario, Canada; 9Erasmus Medical Center,

Rotterdam, Netherlands; 10Vall d’Hebron Hospital, Barcelona, Spain

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TAF: Week 96-120 Open Label Study Design* GS-US-320-0108 and GS-US-320-0110

*Study has been amended to extend the double blind to Week 144 and open-label to Week 384 (Year 8) 15

120 144

TAF 25 mg QD

TDF 300 mg QD

0 384


48 Week 96

n=435

n=211

TAF 25 mg QD

TDF 300 mg QD

n=361

n=180

Data Cut

Two Phase 3, randomized, double-blind, active-controlled trials

– Study 108 (N=425): HBeAg-negative patients

– Study 110 (N=873): HBeAg-positive patients

Key inclusion criteria (both studies)

– HBV DNA ≥20,000 IU/mL; ALT >60 U/L (males) >38 U/L (females); eGFR ≥50 mL/min

2:1 randomization

– Stratified by HBV DNA level and treatment status (naïve/experienced)


Chan HLY et al. EASL 2017 PS-041

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88 88

0

20

40

60

80

100

47

63

0

20

40

60

80

100

Efficacy HBV DNA and ALT Normalization

16

120

weeks

96

weeks

TDF → TAF TDF

83/

176

106/

167

ALT Normalization

AASLD Laboratory Criteria

p<0.001

156/

177

HB

V D

NA

<29 I

U/m

L, %

148/

169

HBV DNA <29 IU/mL

120

weeks

96

weeks

Viral suppression was maintained and ALT normalization rate increased upon switch from TDF to TAF

% A

LT

Norm

aliz

ed

17

-6

-5

-4

-3

-2

-1

0

1

2

Creatinine clearance change from Week 0-96 Creatinine clearance change from Week 96-120

Renal Laboratory Parameters in CHB Patients Treated with TDF Switched to TAF

17 CrCl, creatinine clearance.

TDF TDFTAF

Me

dia

n C

ha

ng

e in

Cre

atin

ine

Cle

ara

nce

mL

/min

Significant improvement in CrCl was observed at 24 Weeks after switching from

TDF to TAF

Δ= 1.2

Δ= -4.8

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Δ= -3.06

Δ= 1.48

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

BMD change from Week 0-96 BMD change from Week 96-120

Δ= -2.69

Δ= 0.59

-3.5

-3

-2.5

-2

-1.5

-1

-0.5

0

0.5

1

1.5

2

BMD change from Week 0-96 BMD change from Week 96-120

Changes in BMD in CHB Patients Treated with TDF Switched to TAF

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Significant improvements in hip and spine BMD were observed at Week 120 in patients who switched from TDF

to TAF at 96 Weeks

Spine Hip

TDF TDFTAF TDF TDFTAF 2.0

1.5

1.0

0.5

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

Me

an

% C

ha

ng

e

In B

MD

, g

/cm

2

2.0

1.5

1.0

0.5

0

-0.5

-1.0

-1.5

-2.0

-2.5

-3.0

-3.5

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Hepatitis C: Special Populations

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GLE/PIB in HCV GT 1, 2, 4, 5, or 6 with Cirrhosis

Phase 3, single arm, open-label study in HCV GT 1, 2, 4, 5, or 6 TN/TE* patients with compensated cirrhosis; GT 3 patients were not included

EXPEDITION-1

Glecaprevir (GLE, formerly ABT-493; NS3/4A inhibitor); pibrentasvir (PIB, formerly ABT-530; NS5A inhibitor). Dosed as 3 tablets for a total of 300mg/120 mg *TE= IFN, pegIFN±RBV or SOF+RBV±PegIFN Forns, EASL 2017, GS-006

N=146

Age, median years (range) 60 (26-88)

Male, n (%) 90 (62)

White race*, n (%) 120 (82)

HCV RNA, median log10 IU/mL (range) 6.1 (3.1-7.4)

GT 1 / 2 / 4 / 5 / 6, (%) 60 / 23 / 11 / 1 / 5

Treatment-exp, % 25

IFN-based (IFN/PegIFN±RBV) 25 (69)

SOF-based (SOF+RBV±PegIFN) 11 (31)

Child-Pugh score 5 at screening 133 (91)

Week 0 Week 12 Week 24

N=146 GLE/PIB SVR12 99% (145/146)

GLE exposure was 2.2-fold higher in cirrhotic patients than those without cirrhosis

* Race and ethnicity are self-reported

N=146

Any AE 101 (69)

Any serious AE 11 (8)

Common AEs (occurring in ≥10% of patients)

Fatigue 28 (19)

Headache 20 (14)

Pruritus 15 (10)

DC due to AE 0

Relapse: GT1a (PT W8) Demographics

Safety

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Summary: In HCV patients with CKD stages 1-5, EBR/GZR was observed to be highly effective with an overall SVR 12 (PP) of 99% (142/144) and and SVR 12 (PP) of 100% (79/79) in patients with sever to end stage CKD (Stage 4 to 5)

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Hepatitis C: Prior DAA Failures

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Rationale

• Individuals who have failed a direct-acting antiviral (DAA) containing regimen represent a growing unmet medical need

• This population may have a higher prevalence of negative predictors such as cirrhosis, prior interferon treatment, and baseline or selected resistance-associated substitutions (RASs), including dual or multi-class RASs.

• No approved therapies for NS5A experienced patients

• Treatment emergent NS5A RAS may persist for years

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GLE/PIB for 12 or 16 Weeks in HCV GT 1,4,5 or 6 and Prior DAA Failure

Randomized, open-label study in GT 1,4 5 or 6 and prior DAA treatment failure to NS5A and/or NS3/4A protease inhibitors

MAGELLAN-1, Part 2

Glecaprevir (GLE, formerly ABT-493; NS3/4A inhibitor); pibrentasvir (PIB, formerly ABT-530; NS5A inhibitor). Dosed as 3 tablets for a total of 300mg/120 mg Poordad, EASL 2017, PS-156

Baseline Demographics N=91

GLE/PIB 12 weeks, n 44

GLE/PIB 16 weeks, n 47

Male, % 70

Mean BMI, kg/m2 29.3

Baseline HCV RNA log10 IU/mL 6.1

GT 1a / 1b / 4, % 74 / 21 / 4

Compensated cirrhosis, % 30


GLE/PIB SVR12

Week 12

GLE/PIB SVR12

Week 24

No D/C due to AE; no SAEs related to study drug

89%

91%

SVR12

Prior Treatment Regimen N=91

PI (no NS5A) 27

NS5A (no PI) 34

NS5A + PI 30

VF

11%

9%

N=44

N=47

30

89 91 100 100

88 94

79 81

0

10

20

30

40

50

60

70

80

90

100

12 Weeks 16 Weeks

% P

atie

nts

Ach

ievi

ng

SVR

12

Overall PI-experienced

NS5A inhibitor-experienced PI+NS5A inhibitor-experienced

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9/91 patients had virologic failure − 9/9 had NS5A resistance at baseline − 4/9 had NS3 resistance at baseline

44% (4/9) treatment failures resulted in multiclass NS3 and NS5A RASs 100% (9/9) treatment failures resulted in multipositional NS3 and/or NS5A RASs

OTVF, on-treatment virologic failure; Glecaprevir (GLE, formerly ABT-493; NS3/4A inhibitor); pibrentasvir (PIB, formerly ABT-530; NS5A inhibitor). Dosed as 3 tablets for a total of 300mg/120 mg; Analysis excluded 3 SVR-achieving patients in the 16-week arm who did not have available sequences (1 was PI only-experienced and 2 were NS5A inhibitor-only experienced). Substitutions at positions 155, 156, 168 in NS3 and 24, 28, 30, 31, 58, 92, 93 in NS5A relative to the subtype specific reference sequence were included in the analysis.

GLE/PIB SVR12 rates by baseline substitutions and prior DAA therapy

MAGELLAN-1, Part 2

SVR12 Rate by DAA Class in Prior Therapy

39 44

14 14

14 16

11 14

43 47

13 13

17 18

13 16

1 OTVF 1 Relapse

3 Relapse 1 OTVF 1 OTVF

Poordad, EASL 2017, PS-156 Pilot-Matias, EASL 2017, SAT-204

100 100 100 100

83

96

80

25

0

10

20

30

40

50

60

70

80

90

100

12 Weeks 16 Weeks

% P

atie

nts

Ach

ievi

ng

SVR

12

None NS3 only NS5A only NS3 + NS5A

13 13

2 2

20 24

4 5

13 13

4 4

22 23

1 OTVF 1 OTVF

3 Relapse 1 Relapse

SVR12 Rate by Presence of Baseline Substitutions

1 4

3 OTVF

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Safety and efficacy of the fixed-dose combination regimen of Uprifosbuvir (MK3682)/Grazoprevir/Ruzasvir in cirrhotic or non-cirrhotic patients with chronic HCV GT1 infection who previously failed a direct-acting antiviral regimen (C-Surge) Heiner Weidemeyer, David Wyles, K. Rajender Reddy, et al.

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Grazoprevir + Ruzasvir + Uprifosbuvir + RBV for 16 weeks or – RBV for 24 weeks in G1 prior DAA Failure (SOF/LDV or EBR/GZR)


GZR/RZR/UPR SVR12

GZR/RZR/UPR SVR12

Week 24

98%

100%

SVR12 VF

0%

0%

N=45

N=49

Week 36

0

10

20

30

40

50

60

70

80

90

At leastone NS5A

One NS5A Two NS5A Three ormoreNS5A

At leastone NS3

DualNS5A and

NS3

Summary: GZR/RZR/UPR was highly effective in G1 patients Who previously failed an NS5A inhibitor No impact of cirrhosis High efficacy despite a large number of baseline RAS in this population

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Demographics

Roberts, EASL 2017, SAT-280

Patients, n (%)

DAA-Experienced Patients SOF/VEL/VOX 12 weeks

n=445

DAA-Naïve Patients SOF/VEL/VOX 8 Weeks

n=611

GT 1 / 2 / 3 / 4 / 5 / 6, % 51 / 8 / 30 / 9 / <1 / 1 38 / 10 / 33 / 10 / 3 / 5

Cirrhosis 205 (46) 200 (33)

Platelet count <100 x 103/µL 61 (14) 51 (8)

FibroScan ≥12.5 kPa* 139 (31) 151 (25)

Prior NS5A inhibitor experience 262 (59) n/a

Prior PEG/RBV experience n/a 128 (21)

Baseline HCV RNA ≥800,000 IU/mL 326 (73) 416 (68)

USA 236 (53) 333 (54)

POLARIS 1-4: Integrated efficacy analysis of SOF/VEL/VOX in DAA-experienced or naïve patients treated for 8 or 12 weeks

The POLARIS program enrolled a diverse population of patients, including many with factors historically associated with treatment failure

*Patients without FibroScan scores are included in denominator.

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Efficacy of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients

Breakthrough 1* 1 1 0 0 0 0 0 0 0

Relapse 7 2 2 0 0 4 1 0 0 0

Other 6 3 2 1 0 2 1 0 0 0

*Patient had drug levels consistent with nonadherence. Roberts, EASL 2017, SAT-280

97 97 97 99 100 96 95 100 100 100

0

20

40

60

80

100

SV

R1

2, %

GT 4

1

1

431

445

150

155

36

36

126

132

39

41

222

228

Total GT 1

Total

GT 1a GT 1b GT 2 GT 3 GT 5 GT 6 Other

1

1

6

6

68

69

The SVR12 rate was 97% (431/445) in DAA-experienced patients treated with SOF/VEL/VOX for 12 weeks; Rates were similar regardless of genotype

35

Resistance Analysis of SOF/VEL/VOX for 12 Weeks in DAA-Experienced Patients

Sarrazin, EASL 2017, THU-248

SVR12 in DAA-Experienced Patients With and Without RASs By HCV GT

98 100 99 100 99 100 94

97 100 100

94 97

0

20

40

60

80

100

GT 1 GT 2 GT 3 GT 4–6

No RASs Any RASs NS3 RASs NS5A RASs NS3 + NS5A RASs

41 42

173 175

43 45

59 59

69 71

8 8

23 23

3 3

23 23

3 3

69 70

50 53

47 50

2 2

9 9

36 37

31 32

No impact of RAS on the SVR12 rate in DAA-experienced patients treated with SOF/VEL/VOX for 12 weeks

36

HCV Treatment in Children

37

LDV/SOF ± RBV in Children 6–11 Years Old

LDV/SOF 45/200 mg tablet; RBV dosed using a weight-based algorithm. Murray, EASL 2017, PS-101

Open-label study of LDV/SOF (45 mg/ 200 mg) fixed dose combination tablet (once daily) ± RBV (15 mg/kg/day up to 1400 mg/day) for 12 or 24 weeks in children aged 6 to 11 years

LDV/SOF ± RBV n=90

Mean age, y (range) 9 (6–11)

Male, n (%) 53 (59)

White, n (%) 71 (79)

HCV GT 1 / 3 / 4, % 96 / 2 / 2

Mean baseline HCV RNA, log10 IU/mL (range)

6.0 (4.6–7.3)

Treatment experienced, n (%) 18 (20)

Cirrhosis, n (%) 2 (2) S

VR

12

, %

99 100 100

0

20

40

60

80

100

LDV/SOF12 Wk

LDV/SOF24 Wk

LDV/SOF+RBV24 Wk

86/87 1/1 2/2

1 relapse

Half dose LDV/SOF ± RBV resulted in high SVR12 rates and was well tolerated in 6 to 11 years old patients

Grade 2 AEs: Dental abscess, abdominal pain, gastroenteritis. None were considered drug related

No treatment DC due to AE

Baseline Demographics SVR12

38

Summary

• Important data regarding increasing co-morbidities in our HBV population

• Excellent safety of TAF with a message that switching from Tenofovir to TAF may be beneficial in our HBV patients

• Combinations are coming (late summer) which will be able to address our patients with cirrhosis, renal failure, prior treatment failure

• Given the safety of these combinations, treatment of children will likely be possible

EASL UPDATE Viral Hepatitis - Swedish

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