Therapeutic Strategies for HCV Non-Genotype 1 · 2015-06-22 · Genotype 3 HCV Treatment-Naive Pts...

Therapeutic Strategies for

HCV Non-Genotype 1

Fred Poordad, MDProfessor of Medicine

Chief, Hepatology

University of Texas Health Science Center

Vice President, Academic and Clinical Affairs

The Texas Liver Institute

San Antonio, Texas

Disclosures

• Dr. Poordad has received grant/research support from AbbVie,

Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex

Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb,

Genentech, Gilead Sciences, GlaxoSmithKline,

GlobeImmune, Idenix Pharmaceuticals, Idera

Pharmaceuticals, Intercept Pharmaceuticals, Janssen,

Medarex, Medtronic, Merck, Novartis, Santaris

Pharmaceuticals, Scynexis Pharmaceuticals, Vertex

Pharmaceuticals, and ZymoGenetics

Overview

• Genotype non 1 HCV

• Scope of the problem

• Who is the ‘hard-to-cure’ population?

• Is there truly one regimen and duration for everyone?

Distribution and Prevalence of HCV Genotypes: Genotype 1b is most common worldwide, followed by G3

Messina JP et al, Hepatology, 2015; 61: 77-87.

Geno 2/3 Therapy Today

98

82

91

62

61

71

34 30

0

20

40

60

80

100

SOF + RBV PEG-IFN + RBV

GT 2 GT 3

SV

R12 (

%)

No cirrhosis No cirrhosisCirrhosis Cirrhosis

58/59 44/54 10/11 8/13 89/145 99/139 13/38 11/37

SOF + RBV vs PEG + RBV in G2 and G3: FISSION

SVR12 by HCV Genotype and Cirrhosis Status

Lawitz et al. 2014

Wk 0 Wk 24 SVR4, SVR12, SVR24

Placebo*(n = 85)

Sofosbuvir + Ribavirin (n = 250)

Sofosbuvir + Ribavirin(n = 84)*

*Protocol amended to eliminate placebo arm and to extend treatment duration to 24 weeks for patients with genotype 3 HCV irrespective of prior treatment history.

Wk 12

VALENCE: Study Design

Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001

94 92 87

60

0

20

40

60

80

100

SV

R12

(%

)

Naïve,

Noncirrhotic

Naïve,

CirrhoticExperienced,

Noncirrhotic

Experienced,

Cirrhotic

86/92 12/13 27/4587/100

SVR12 in GT 3 Patients Treated for 24 Weeks

Zeuzem S, et al. N Engl J Med. 2014;370:1993-2001

AASLD/IDSA Recommendations for Genotype 2 HCV Treatment-Naive Pts

• Alternative regimens: none

• Regimens specifically not recommended:

– PegIFN/RBV x 24 wks

– Monotherapy with pegIFN, RBV, or DAA

– TVR-, BOC-, SMV-based regimens

AASLD/IDSA treatment recommendations.

PopulationRecommended

RegimenDuration

Treatment naive and

previous relapsers,

genotype 2

Sofosbuvir 400 mg

+

RBV 1000-1200

mg/day

12 wks

• Regimens specifically not recommended:

– PegIFN/RBV ± TVR or BOC

– Monotherapy with pegIFN, RBV, or DAA

*Pts with cirrhosis may benefit by extension of therapy to 16 wks.


RegimenDuration

Nonresponse to previous treatment with pegIFN/RBV

Sofosbuvir 400 mg + RBV 1000-1200 mg/day

12 wks*


RegimenDuration

Nonresponse to previous

treatment with

pegIFN/RBV with IFN

eligibility

Sofosbuvir 400 mg +

pegIFN +

RBV 1000-1200 mg/day

12 wks

AASLD/IDSA Recommendations for Genotype 2 HCV Treatment-Experienced Pts


AASLD/IDSA Recommendations for Genotype 3 HCV Treatment-Naive Pts

• Not recommended:– PegIFN/RBV for 24-48 wks

– Monotherapy with pegIFN, RBV, or a DAA

– Telaprevir, boceprevir, simeprevir



RegimenDuration

Regardless of IFN

eligibility

Sofosbuvir 400 mg +

RBV 1000-1200

mg/day

24 wks


RegimenDuration

Only consider if eligible

for IFN

Sofosbuvir 400 mg +

pegIFN +

RBV 1000-1200

mg/day

12 wks

AASLD/IDSA Recommendations for Genotype 3 HCV Treatment-Experienced

• Not recommended:

– PegIFN/RBV ± telaprevir, boceprevir, simeprevir

– Monotherapy with pegIFN, RBV, or a DAA



RegimenDuration

Regardless of IFN eligibilitySofosbuvir 400 mg +

RBV 1000-1200 mg/dayRegardless of IFN eligibility


RegimenDuration

Consider only if eligible for IFN

Sofosbuvir 400 mg + pegIFN

+ RBV 1000-1200 mg/day

12 wks

Daclatasvir + SofosbuvirN=101Treatment Naïve19% w/cirrhosis

ALLY-3Weeks0 12 24

N=51

90%

86%

SVR

Daclatasvir + SofosbuvirPrior Treatment25% w/cirrhosis

• Key demographics: Cirrhosis= 21%, Prior SOF failures = 7

• Most AE mild fatigue, headache, nausea, diarrhea

• Relapse occurred in 16/152 (11%), most relapsers were cirrhotic

SVR F0-F3 = 96% (105/19)

SVR F4 = 63% (20/32)

All-Oral 12-week Combination of Daclatasvir (NS5A) and

Sofosbuvir (NUC) in Patients with Genotype 3: ALLY-3

Nelson, AASLD 2014, LB-3

SOF + PegIFN + RBV 1000-1200 mg SVR12

0 12 24Study Week

GT 2/3 TE

N=47

Open-label, Phase 2 study of the efficacy of SOF + PegIFN + RBV for 12 weeks in

treatment-experienced patients with GT 2 or 3

Mean age (range), y 56 (39‒72)

Male, n (%) 32 (68)

White, n (%) 45 (96)

Hispanic, n (%) 21 (45)

Mean BMI (range), kg/m2 31 (21‒53)

IL28B CC, n (%) 17 (36)

HCV GT 3, n (%) 24 (51)

Mean BL HCV RNA (range), log10 IU/mL 6 (4‒7)

Cirrhosis, n (%) 26 (55)

Prior relapse/breakthrough, n (%) 40 (85)

Lawitz E, et al. AASLD 2013. Washington, DC. Oral #LB-4

LONESTAR-2 Study Design and Demographics

96 100 93

0

10

20

30

40

50

60

70

80

90

100

GT 2

SV

R1

2 (

%)

Overall

Non-cirrhotic

Cirrhotic

22/23 9/9 13/14*

*The 1 cirrhotic patient who did not achieve SVR prematurely discontinued therapy without <LLOQ

LLOQ, lower limit of quantification


SOF + PegIFN + RBV in HCV GT 2 Treatment-Experienced

Patients LONESTAR-2 Virologic Response

83 83 83

0

10

20

30

40

50

60

70

80

90

100

GT 3

SV

R1

2 (

%)

Overall

Non-cirrhotic

Cirrhotic

20/24* 10/12 10/12

*2 relapses; 2 lost to follow-up


SOF + PegIFN + RBV in HCV GT 3 Treatment-Experienced

Patients LONESTAR-2 Virologic Response

SOF/RBV/PegIFN for 12 Weeks vs. SOF/RBV for 16 or 24 Weeks in GT 2 or 3

Foster G, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. LO5.

n=196 SOF + RBV SVR12

n=199 SOF + RBV SVR12

n=197 SOF + PEG/RBV SVR12

Wk 0 12 16 24 28 36

SOF + RBV16 weeks

n=196

SOF + RBV24 weeks

n=199

SOF + PEG/RBV12 weeks

n=197Total

n=592

Mean age, y (range) 51 (20-69) 49 (23-71) 50 (19-73) 50 (19-73)

Male, n (%) 134 (68) 129 (65) 132 (67) 395 (67)

Asian, n (%) 28 (14) 26 (13) 25 (13) 79 (13)

Mean BMI, kg/m2 (range) 28 (18-50) 28 (18-55) 28 (19-45) 28 (18-55)

IL28B CC, n (%) 75 (38) 73 (37) 78 (40) 226 (38)

HCV genotype 3, n (%) 181 (92) 182 (92) 181 (92) 544 (92)

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

6.3 (4.0-7.6) 6.2 (3.3-7.6) 6.3 (3.7-7.5) 6.3 (3.3-7.6)

Treatment experienced, n (%) 105 (54) 105 (53) 103 (52) 313 (53)

Cirrhosis, n (%) 72 (37) 73 (37) 74 (38) 219 (37)

SVR12


87

71

100

84

9493

0

20

40

60

80

100

GT 2 GT 3

SVR

12

(%

)

SOF + RBV 16 weeks SOF + RBV 24 weeks SOF + PEG/RBV 12 weeks

13/15 17/17 15/16 128/181 153/182 168/181

83

57

76

47

90 82 82

77

96 91 9486

0

20

40

60

80

100

No Cirrhosis Cirrhosis No Cirrhosis Cirrhosis

SVR

12

(%

)

5870

6572

6871

1221

1822

2123

4154

4454

4952

1736

2634

3035

Treatment Naïve Treatment Experienced


SVR12 By Prior Treatment and Cirrhosis

Safety


Patients, n (%)

SOF + RBV16 weeks

n=196

SOF + RBV24 weeks

n=199

SOF + PEG/RBV12 weeks

n=197

Overall Safety

AEs 185 (94) 188 (95) 195 (99)

Grade 3-4 AE 11 (6) 7 (4) 15 (8)

Serious AE 8 (4) 10 (5) 12 (6)

Treatment D/C due to AE

3 (2) 2 (1) 1 (<1)

Death 0 0 0

LaboratoryAbnormalities

Grade 3-4 30 (15) 29 (15) 74 (38)

Hb <10g/dL 7 (4) 12 (6) 24 (12)

Hb <8.5 g/dL 0 0 2 (1)

Platelets <50,000/mm3 1 (<1) 0 9 (5)

C-WORTHY: Study Design

• Treatment-naive patients with HCV GT3 infection

• Cirrhotic and HIV coinfected patients excluded

• Randomized 1:1

• Treatment durations of 12 or 18 weeks

• All patients received weight-based ribavirin

GZR 100 mg / EBR 50 mg / RBV

D1 TW4 TW8 TW12 TW18

Follow-up: Primary endpoint: SVR12

HCV RNA < 25 IU/mL (COBAS TaqMan V2.0 [LoQ 25 IU/mL])

FW4 FW8 FW12

GZR 100 mg / EBR 50 mg / RBVn=21

n=20

Gane E, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0776.

45%(23.1, 68.5)

57.1%(34.0, 78.2)

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

HC

V R

NA

<1

5 IU

/mL

(%, 9

5%

CI)

C-WORTHY: SVR12 Results

Non-virologic failure, n

1 2

Rebound, n 3 2

Breakthrough, n 6 5

Futility, n 1 0

Relapse, n 0 0

920

1221

GZR + EBR + RBV 12 weeks

GZR + EBR + RBV 18 weeks

Gane E, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0776.

Intention to Treat

C-SWIFT: SVR Results - HCV 3

93 100 91

0

10

20

30

40

50

60

70

80

90

100

HC

V R

NA

<1

5 IU

/mL

(%, 9

5%

CI)

1415

Non-cirrhotic

Cirrhotic

1011

1414

Treatment Duration 8 Weeks 12 Weeks 12 Weeks

Breakthrough 0 0 0

Relapse 1 0 1

Early discon. 0 0 1*

Poordad F, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. O006.

Modified Intent To Treat Analysis

SVR12 by HCV Genotype

24

SVR12 by HCV Genotype in Ally-1

76

9710090

80 8391

100 100

0

20

40

60

80

100

SVR

12

, %

1a 1b 2 3 4 6

Genotype

1a 1b 2 3 4 6

Advanced cirrhosis cohort N = 60

Post-transplant cohort N = 53

Poordad, et al. EASL 2015

SVR12 48-Week Follow-up

SVR1248-Week Follow-up

Week 72Week 60Week 36Week 24Week 12Day 0

OBV/PTV/r with RBV in HCV GT4 +/- Cirrhosis

Doss W, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P1351.

Arm B• GT4 treatment-naïve and treatment-experienced with

compensated cirrhosis• n=30

Arm C• GT4 treatment-naïve and treatment-experienced with compensated

cirrhosis• n=30

Arm A• GT4 treatment-naïve and treatment-experienced with

compensated cirrhosis• n=30

Treatment-Naïve Treatment-Experienced

RVR

SVR4

SVR12

100100 100 10010097.6

Pat

ien

ts (

%)

41/42 42/42 42/42 49/49 49/49 49/49

PEARL-I: Efficacy of OBV/PTV/r + RBV in Treatment-Naïve and Treatment-Experienced Noncirrhotic Subjects With GT4 Infection

LDV/SOF for GT4 or GT5 HCV Infection

Aberel A, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. O056.

Genotype 4 Genotype 5

Naïven=22

Experienced n=22

Naïven=21

Experienced n=20

Mean age, years (range) 52 (21-69) 50 (30-62) 61 (40-78) 64 (50-79)

Male, n (%) 11 (50) 17 (77) 11 (52) 10 (50)

White, n (%) 19 (86) 17 (77) 21 (100) 20 (100)

Mean BMI, kg/m2 (range) 25 (19-35) 25 (20-36) 24 (18-30) 27 (19-39)

Cirrhosis, n (%) 1 (5) 9-(41) 3 (14) 6 (30)

IL28B non-CC, n(%) 15 (68) 21 (95) 8 (38) 14 (70)

Mean HCV RNA, log10 IU/ml (range)

6.0 (5.1-6.8) 6.3 (5.6-7.5) 6.2 (5.3-6.9) 6.6 (5.7-7.1)

Genotype 4 Genotype 5

96 91 95 9791

100 9589

0

20

40

60

80

100

TN TETreatment Status

No YesCirrhosis

TN TETreatment Status

No YesCirrhosis

Pat

ien

ts (

%)

21/22 20/22 31/22 10/10 20/21 19/20 31/32 8/9

GZR 100mg / EBR 50mg / RBV

GZR 100mg / RBV

GZR 100mg / EBR 50mg / RBV

C-SCAPE: Study Design

• Treatment-naive, GT2, 4, 5, 6 • Non-cirrhotic, HCV monoinfected • G2 patients assessed for a polymorphism at amino position 31 within

NS5A – Preclinical data demonstrate a lower potency for EBR in methionine (M)

compared to leucine (L) at position 31

D1 TW4 TW8 TW12 FUW4 FUW8 FUW12

GZR 100mg / EBR 50mg

Follow-up: Primary endpoint: SVR12

HCV RNA < 25 IU/mL (COBAS TaqMan V2.0 [LoQ 15 IU/mL])

Patients per arm (n)

G2 G4 G5 G6 ALL

30 - - - 30

30 - - - 30

- 10 4 5 19

- 10 4 5 19

Brown A, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0771.

100 100 7590 25 75

GZR / EBR + RBV for 12 weeks

GZR + EBR for 12 weeks

80 73

0

25

50

75

100

Pat

ien

ts (

%)

GZR / EBR + RBV for 12 weeks

GZR + RBV for 12 weeks

C-SCAPE: SVR12 Results

Genotype 2 Genotype 4 Genotype 5 Genotype 6

Relapse (n) 3 3 0 0 0 2 1 0

Breakthrough (n) 1 3 0 0 0 1 0 1

Futility (n) 0 1† 0 0 0 0 0 0

LTFU/Admin discon (n) 2 0 0 1 0 0 0 0

24/30

19/26*

3/4*

3/4*

10/10

9/10

4/4

1/4

Brown A, et al. 50th EASL; Vienna, Austria; April 22-26, 2015. Abst. P0771.

(Modified Intent to Treat)

Summary

• We currently have good therapy for geno 2, but it uses RBV

– Geno 2 cirrhotics can be challenging

• Geno 3 is the biggest challenge, esp cirrhotics

• Geno 4 responds well to most regimens

• Geno 5 has very little data

• Geno 6 appears to respond much like geno 1

Conclusion

• We may never have one therapy for all genotypes

• Small SVR differences between regimens will dictate how we treat them

• Cirrhotics clearly are different and need either longer duration, or different regimens in some cases

Therapeutic Strategies for HCV Non-Genotype 1 · 2015-06-22 · Genotype 3 HCV Treatment-Naive Pts...

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