New treatments in the era of HCV infection

Maria Buti

Hospital Universitario Valle Hebron. Barcelona. Spain

Disclosures

I have received honoraria as a speaker or a member of a speaker bureau or as an advisor or consultant or have received grants for clinical research from:

• AbbVie, BMS, Gilead, Janssen, and MSD

Next-generation HCV treatments can offer several clear advantages compared with currently approved regimens

What characteristics are most desirable for next-generation HCV treatments?

Pan-genotypic (GT1–6)

Shorter treatment durations

Limited drug–drug interactions

Highly efficacious in most populations

including “difficult-to-treat” patients

High barrier to resistance

Convenient dosing with co-formulated

pills

RBV sparing

Next-generation drugs for HCV treatment

NS3/4AProtease inhibitor

NS5A

ABT-493

ABT-530

Velpatasvir

GS-9587

Elbasvir

Grazoprevir

NS5B polymerase

Sofosbuvir

MK-3682

MK-8408

ABT-493 (NS3/4A PI) + ABT-530 (NS5A inhibitor)

SURVEYOR-I + -II study overview

Poordad F, et al. Hepatology 2015; 62(Suppl):228A (oral presentation);Wyles DL, et al. Hepatology 2015; 62(Suppl):339A (oral presentation).

Phase 2 – SURVEYOR clinical study overview

Pan-genotypic

ABT-493 ABT-530

NS5A inhibitor

Pan-genotypic

NS3/4A protease inhibitor

SURVEYOR-II

SURVEYOR-IABT-493 + ABT-530

± RBV(8–12 weeks)

ABT-493 + ABT-530± RBV

GT1GT4, 5, or 6

(non-cirrhotic)

Cirrhotic or non-cirrhotic, treatment-naive or pegIFN/RBV null-responders

GT2 or GT3Cirrhotic or non-cirrhotic,

treatment-naive or pegIFN/RBV failures

Primary completion date:*

March 2016

Primary completion date:*

February 2016

SURVEYOR-I: High SVR rates in HCV GT1 non-cirrhotic, treatment-naive, or pegIFN/RBV null-responders (Part 1)

* 1 patient experienced a decrease in blood phosphorus considered to be related to the study drugs.Poordad F, et al. Hepatology 2015;

62(Suppl):228A (oral presentation).

SVR12

100 97

0

20

40

60

80

100

ABT-493 200 mg +ABT-530 120 mg

ABT-493 200 mg +ABT-530 40 mg

HCV GT1, treatment-naive, or pegIFN/RBV null-responder, non-cirrhotic patients received ABT-493 + ABT-530 for 12 weeks (N=79)

81% GT1a 37% pegIFN/RBV null-responders

12 weeks

100% treatment-experienced and 98% -naive patients achieved SVR12

All patients with baseline NS3 and/or NS5A variants achieved SVR12

1 patient reported an SAE (not related to study drug)

3 patients had severe AEs*

SVR

12

(%

)

4040

3839

SURVEYOR-I: HCV GT1, non-cirrhotic, treatment-naive, or pegIFN/RBV treatment-experienced (Part 2)

* Due to abdominal adenocarcinoma. Poordad F, et al. Hepatology 2015; 62(Suppl):1388A (poster presentation).

ABT-493 300 mg + ABT-530 120 mg

HCV GT1, treatment-naive, or pegIFN/RBV-experienced, non-cirrhotic patients received ABT-493 + ABT-530 for 8 weeks (N=34)

97% SVR12 with 8 weeks of treatment

All patients with baseline NS3 and/or NS5A variants achieved SVR12

1 patient discontinued at Week 4* (not related to study drugs)

100 97

0

20

40

60

80

100

SVR4 SVR12

3434

3334

8 weeks

SVR

(%

)

71% GT1a15% pegIFN/RBV

treatment-experienced

SURVEYOR-II: High SVR rates with ABT-493 + ABT-530 in non-cirrhotic, treatment-naive, and -experienced patients with HCV GT2 infection

* Atrial fibrillationLTFU = lost to follow up. Wyles DL, et al. Hepatology 2015; 62(Suppl):339A (oral presentation).

HCV GT2, treatment-naive, or pegIFN/RBV failures, non-cirrhotic patients received ABT-493 + ABT-530 ± RBV for 12 weeks (N=75)

96 100 100

0

20

40

60

80

100

300 mg+

120 mg

200 mg+

120 mg

200 mg+

120 mg+

RBV

SVR

12

(%

) HCV GT2

1 LTFU

2425

2424

2525

1 patient had an SAE

(not related to study drugs)

No virologic failures in 74 patients

All patients with baseline NS3 or NS5A variants achieved SVR12

ABT-493+

ABT-530

SURVEYOR-II: High SVR rates with ABT-493 + ABT-530 in non-cirrhotic, treatment-naive, and -experienced patients with HCV GT3 infection

*2 study drug-related severe AEs were reported: decreased hemoglobin (+ RBV); blood Creatinine phosphokinase increased (ABT-493 200 mg + ABT-530 40 mg arm).

Kwo P, et al. Hepatology 2015; 62(Suppl):337A (oral presentation).

ITT SVR12 rates

1 patient discontinued due to an AE

7 patients reported severe AEs*

ABT-493 (300 mg QD) and ABT-530 (120 mg QD) have been

selected for further studies

>90% SVR12 rates in

GT3-infected patients

HCV GT3, treatment-naive, or pegIFN/RBV failures, non-cirrhotic patients received ABT-493 + ABT-530 ± RBV for 12 weeks (N=121)

ABT-493+

ABT-530

93 93 94

82

0

20

40

60

80

100

300 mg+

120 mg

200 mg+

120 mg

200 mg+

120 mg+

RBV

200 mg+

40mg

SVR

12

(%

) HCV GT3

2830

2830

2931

2530

GZR/EBR + MK-3682or

GZR + MK-3682 + MK-8408

Phase 2 – Part A of C-CREST-1 & 2: GZR + MK-3682 (NS5B polymerase inhibitor) with either EBR or MK-8408 (NS5A inhibitor) in patients with HCV GT1, 2, or 3 infection

* 100% SVR12 with GZR/EBR + MK-3682 (300 mg or 450 mg) and GZR + MK8408 + MK3682 (300 mg).EBR = elbasvir; GZR = grazoprevir. Gane E, et al. Hepatology 2015; 62(Suppl):1389A (poster presentation).

HCV GT1-, 2-, or 3-infected patients treated for 8 weeks with GZR/EBR + MK-3682 or GZR + MK-8408 + MK-3682

SVR12 rates by regimen

GT1% (n/N)

GT2% (n/N)

GT3% (n/N)

GZR/EBR + MK-3682 (300 mg)

100 (23/23)

69 (11/16)

90 (19/21)

GZR/EBR + MK-3682 (450 mg)

100 (23/23)

60 (9/15)

86 (19/22)

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

100 (24/24)

71 (10/14)

95 (20/21)

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

91 (21/23)

94 (15/16)

91 (20/22)

Treatment-naive Non-cirrhotic

100% SVR12 with 8 weeks of treatment in

GT1-infected patients*

SVR12 100% (21/21) in GT1-infected patients with

baseline NS5A RAVs

Phase 2 – Part A of C-CREST-1 & 2: GZR + MK-3682 (NS5B polymerase inhibitor) with either EBR or MK-8408 (NS5A inhibitor) in patients with HCV GT1, 2, or 3 infection

EBR = elbasvir; GZR = grazoprevir. Gane E, et al. Hepatology 2015; 62(Suppl):1389A (poster presentation).

SVR12 rates by regimen

GT1% (n/N)

GT2% (n/N)

GT3% (n/N)

GZR/EBR + MK-3682 (300 mg)

100 (23/23)

69 (11/16)

90 (19/21)

GZR/EBR + MK-3682 (450 mg)

100 (23/23)

60 (9/15)

86 (19/22)

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

100 (24/24)

71 (10/14)

95 (20/21)

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

91 (21/23)

94 (15/16)

91 (20/22)

SVR12 94% (15/16) in GT2-infected patients with

GZR + MK-8408 + MK3682 (450 mg)

Treatment-naive Non-cirrhotic

94% of GT2-infected patients had baseline

NS5A RAVs

HCV GT1-, 2-, or 3-infected patients treated for 8 weeks with GZR/EBR + MK-3682 or GZR + MK-8408 + MK-3682

Phase 2 – Part A of C-CREST-1 & 2: GZR + MK-3682 (NS5B polymerase inhibitor) with either EBR or MK-8408 (NS5A inhibitor) in patients with HCV GT1, 2, or 3 infection

EBR = elbasvir; GZR = grazoprevir. Gane E, et al. Hepatology 2015; 62(Suppl):1389A (poster presentation).

SVR12 rates by regimen

GT1% (n/N)

GT2% (n/N)

GT3% (n/N)

GZR/EBR + MK-3682 (300 mg)

100 (23/23)

69 (11/16)

90 (19/21)

GZR/EBR + MK-3682 (450 mg)

100 (23/23)

60 (9/15)

86 (19/22)

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

100 (24/24)

71 (10/14)

95 (20/21)

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

91 (21/23)

94 (15/16)

91 (20/22)

>90% SVR12 in GT3-infected patients with

GZR + MK-8408 + MK3682 (300 or 450 mg)

Treatment-naive Non-cirrhotic

47% of GT3-infected patients had baseline

NS5A RAVs

HCV GT1-, 2-, or 3-infected patients treated for 8 weeks with GZR/EBR + MK-3682 or GZR + MK-8408 + MK-3682

Sofosbuvir/velpatasvir

99 99 100 100 97 100

0

20

40

60

80

100

Overall GT1 GT2 GT4 GT5 GT6

ASTRAL-1: SOF/VEL in HCV GT1, 2, 4, 5, or 6 in treatment-naive or -experienced patients with or without cirrhosis

VEL = velpatasvir (GS-5816).Feld JJ, et al. Hepatology 2015; 62(Suppl):1379A–1380A (abstract LB-2);

Feld JJ, et al. N Engl J Med 2015; ePub ahead of print].

HCV GT1-, 2-, 4-, or 6-infected patients were randomized to receive SOF/VEL (400 mg/100 mg) or placebo for 12 weeks; HCV GT5-infected patients received SOF/VEL (400 mg/100 mg) for 12 weeks

32% treatment experienced (includes pegIFN/RBV and PI + pegIFN/RBV failures)

19% compensated cirrhosis

2 GT1 patients relapsed, no GT2, 4, 5, or 6 patients relapsed

Frequency and severity of AEs and laboratory abnormalities were similar between SOF/VEL and placebo groups

741 patients enrolled at 81 sites in North America, Europe, and Hong Kong

SOF/VEL for 12 weeks

618624

nN

323328

104104

116116

3435

4141

Overall 99% SVR12

The presence of NS5A RAVs did not impact SVR12 (99% [255/257])

SVR

12

(%

)

ASTRAL-2: SOF/VEL or SOF + RBV for 12 weeks in HCV GT2-infected patients

VEL = velpatasvir (GS-5816); FDC = fixed dose combination.Sulkowski MS, et al. Hepatology 2015; 62(Suppl S1):313A (abstract 205);

Foster GR, et al. N Engl J Med 2015; ePub ahead of print.

1 patient (SOF/VEL) discontinued due to AEs

2 patients died; neither were related to study drugs

The incidence of AEs was lower in the SOV/VEL arm compared with SOF + RBV

15% treatment experienced (with an IFN-containing regimen)

14% compensated cirrhosis

Overall 99% SVR12 with SOF/VEL

The presence of NS5A RAVs did not impact SVR12 (100% [80/80])

269 HCV GT2-infected patients were randomized 1:1 to receive eitherSOF/VEL FDC for 12 weeks (n=134) or SOF + RBV for 12 weeks (n=132)

9994

0

20

40

60

80

100

SOF/VEL12 weeks

SOF + RBV12 weeks

SVR

12

(%

)

133134

nN

124132

6 relapses

ASTRAL-3: SOF/VEL (12 weeks) or SOF + RBV (24 weeks) in HCV GT3-infected patients

VEL = velpatasvir (GS-5816).Mangia A, et al. Hepatology 2015; 62(Suppl S1):338A–339A (abstract 249);

Foster GR, et al. N Engl J Med 2015; ePub ahead of print.

No patients (SOF/VEL) discontinued due to AEs

3 patients died; none were related to study drugs

SVR12 (89% [33/37]) in treatment-experienced, cirrhotic patients

SVR12 (88% [38/43]) in patients with baseline NS5A RAVs

26% treatment experienced(with an IFN-containing regimen)

30% compensated cirrhosis

552 HCV GT3-infected patients received eitherSOF/VEL FDC for 12 weeks (n=277) or SOF + RBV for 24 weeks (n=275)

The incidence of AEs was lower in the SOV/VEL arm compared with SOF + RBV

95

80

0

20

40

60

80

100

SOF/VEL12 weeks

SOF + RBV24 weeks

SVR

12

(%

)

264277

nN

221275

ASTRAL-4: SOF/VEL ± RBV in HCV GT1, -2, -3, -4, or -6 infected patients with decompensated cirrhosis

CP = Child Pugh; MELD = Model For End-Stage Liver Disease;VEL = velpatasvir (GS-5816). * Patients that had received treatment with any NS5A or N55B inhibitor were excluded.

Charlton E, et al. Hepatology 2015;62(Suppl):1387A (poster presentation);

Curry MP, et al. N Engl J Med 2015; ePub ahead of print.

55% treatment experienced(pegIFN/RBV or PI regimen*)

Median CP score 8 (range 5–10) MELD score range 6–24

No RBV RBVAmong patients who

achieved SVR, 47% and 51% had improvements in

CP and MELD scores86

92

75

50

100 100

Overall GT1 GT2 GT3 GT4 GT6

7790

6571

34

612

22

11

SOF/VEL 24 weeks

3.4% (9/267) discontinued due to AEs

9 deaths (all unrelated to SOF/VEL)

HCV GT1-, 2-, 3-, 4-, or 6-infected patients with CP B cirrhosis were randomized to receive SOF/VEL (400 mg/100 mg) for 12 weeks, SOF/VEL + RBV for 12 weeks, or SOF/VEL for 24 weeks

8388

100

50

10094 96

100

85

100

0

20

40

60

80

100

Overall GT1 GT2 GT3 GT4

7590

nN

8287

6068

6568

44

44

714

1113

44

22

SOF/VEL ± RBV 12 weeksSVR

12

(%

)

Summary

Despite the high cure rates observed with currently approved DAA regimens, research into improved

HCV treatments continues

Next-generation HCV treatments may offer several significant advantages compared with currently approved treatments

Efficacy against all HCV genotypes across all patient populations

Convenient co-formulations and reduced pill burdens

Reduced potential for DDIs

High barriers to resistance

Combination regimens in late-stage clinical development have shown high SVR rates across different genotypes, in cirrhotic and non-cirrhotic patients, and in both

treatment-naive and -experienced patients