hepatitis c: emerging therapies

Hepatitis C:

Emerging

Therapies

Educational Objectives

• Identify new compounds currently under investigation for

the treatment of chronic hepatitis C

• Recognize the potential efficacy and safety benefits of

new therapies for chronic hepatitis C currently under

investigation

• Describe how new compounds might fit into the future

treatment armamentarium for chronic hepatitis C

• The International Liver Congress™ 2012 took place

in Barcelona (Spain) April 18 - 22, 2012 at the

Centre Convencions Internacional (CCIB)

• 47th annual meeting of the European Association

for the Study of the Liver

• A record event with 9415 participants

Hepatitis C: Emerging Therapies

http://www2.kenes.com/liver-congress/pages/home.aspx

Goals for Hepatitis C Emerging Therapies

• Compared to PegIFN/RBV, new products should

offer:

– Improved efficacy

– Efficacy in all patient types including previously

treated patients, cirrhotic and black patients

– Orally effective regimen, IFN free

– Shorter treatment duration

– Improved side-effect profile

EASL 2012: The Main Themes

• Several classes of direct-acting antiviral drugs (DAAs) add

efficacy when added to Peg-IFN/RBV

• We have gone from proof of concept that IFN-free

regimens can cure HCV infection to evidence that this can

be accomplished in a very high proportion of patients

• To an unexpected degree, interferon responsiveness

plays a role in mediating response to IFN-free DAA

regimens

• Genotype 1a is more difficult to cure than genotype 1b

with some DAA regimens

Emerging Therapies for the Treatment of

Chronic Hepatitis C, 2012

Compound Manufacturer Activity

ABT-072 Abbott Non-nucleoside NS5B

polymerase inhibitor

ABT-333 Abbott Non-nucleoside NS5B


ABT-450 Abbott/Enanta

NS3 protease inhibitor

ACH-1625 Achillion NS3 protease inhibitor

Asunaprevir

(BMS-650032)

Bristol-Myers Squibb NS3 protease inhibitor

BI201335 Boehringer-Ingelheim NS3 protease inhibitor


Chronic Hepatitis C, 2012 (cont)


BI207127 Boerhinger-Ingelheim Non-nucleoside RNA


Daclatasvir

(BMS-790052)

Bristol-Myers Squibb NS5A replication

complex inhibitor

Danoprevir Roche Macrocyclic NS3/4A

protease inhibitor

GS-7977 (PSI-7977) Gilead (Pharmasset) Uridine nucleotide

analog NS5B


GS-9256 Gilead

NS3 serine protease

inhibitor


Chronic Hepatitis C, 2012 (cont)


Peginterferon

Lambda-1a

Bristol-Myers Squibb Interferon

Tegobuvir Gilead Non-nucleoside NS5B


TMC435 Tibotec/Medvir NS3/4A protease

inhibitor

Not all-inclusive, but indicates drugs covered in this presentation

A 12-Week Interferon-Free Regimen of ABT-450/r, ABT-072,

and Ribavirin was Well Tolerated and Achieved Sustained

Virologic Response in 91% Treatment-Naïve HCV IL28B-CC

Genotype-1-Infected Subject

Lawitz E, Poordad F, Kowdley KV, Jensen D, Cohen DE, Siggelkow

S, Wikstrom K, Larsen L, Menon RM,

Podsadecki T, Bernstein B Abstract 13, Oral Presentation

47th Annual Meeting of the European Association for the Study of

the Liver

Barcelona, Spain

April 19, 2012

12-Week IFN-Free Regimen of ABT-450/r,

ABT-072, and RBV: Objective

• ABT-450 is a potent NS3HCV protease inhibitor

and ABT-072 is a non-nucleoside NS5B

polymerase inhibitor – ABT-450/r indicates dosing with low-dose

ritonavir

• Objective: To assess the safety, tolerability,

pharmaco-kinetics, and antiviral activity of ABT-

450/r, ABT-072, and RBV in treatment-naïve,

non-cirrhotic HCV genotype-1 infected subjects

with IL28B rs12979860 genotype CC

Lawitz E et al. J Hepatol 2012;56(Suppl 2):S7.


ABT-072, and RBV: Methods

• 11 treatment-naïve, non-cirrhotic HCV genotype-

1 infected subjects with IL28B rs12979860

genotype CC enrolled in an open-label study

• 8 genotype 1a, 3 genotype 1b

• Received ABT-450/r 150/100 mg QD + ABT-072

400 mg QD + weight-based RBV 1000-1200

mg/day dosed twice daily for 12 weeks



ABT-072, and RBV: Results

• All 11 subjects completed 12 weeks of treatment and were followed

for 24 weeks post-treatment

– A rapid decrease in HCV RNA level was observed; all subjects

had HCV RNA levels <25 IU/mL by week 3

– All subjects maintained HCV RNA <25 IU/mL from weeks 4

through 12; all had undetectable HCV RNA from weeks 5

through 12

– 10 subjects (91%) achieved SVR24; 1 subject relapsed at post-

treatment week 8. A second subject relapsed 36 weeks post-

treatment; had non-nuc resistant variants

• There were no deaths, serious or severe AEs, or premature

discontinuations

• Most common AEs were mild in severity and included headache,

fatigue, nausea, and dry skin; 2 patients had reversible elevations of

indirect bilirubin



ABT-072, and RBV: Results (cont)


Individual Changes in Plasma HCV RNA (log10 IU/mL)

Through 12 Weeks of Treatment


ABT-072, and RBV: Conclusions


• SVR was achieved in 82% of treatment-naïve,

non-cirrhotic HCV genotype 1-infected subjects

with IL28B CC genotype after 12 weeks of

treatment with ABT-450/r + ABT-072 + RBV

• ABT-450/r + ABT-072 + RBV was well tolerated

• Late relapser emphasizes importance of long

term followup in DAA studies

12-Week Interferon-Free Regimen of ABT-450/r+ABT-

333+Ribavirin Achieved SVR12 in More Than 90% of

Treatment-Naïve HCV Genotype-1-Infected Subjects

and 47% of Previous Non-Responders

Poordad F, Lawitz E, Kowdley KV, Everson GT, Freilich B,

Cohen D, Siggelkow S, Heckaman M, Menon R, Pilot-Matias T,

Podsadecki T, Bernstein B

Abstract 1399, Oral Presentation


the Liver

Barcelona, Spain

April 21, 2012

IFN-Free Regimen of ABT-450/r + ABT-333 + RBV in Treatment-Naïve Genotype-1

HCV Patients: Objective

• ABT-450 is an NS3 HCV protease inhibitor, ABT-

450/r is ABT-450 boosted with low-dose ritonavir,

and ABT-333 is a non-nucleoside NS5B


• Objective: To evaluate the efficacy and safety of

ABT-450/r plus ABT-333 in combination with

RBV in both treatment naïve and treatment-

experienced patients with HCV infection

Poordad F et al. J Hepatol 2012;56(Suppl 2):S549-S550.


HCV Patients: Methods

• Open-label study of HCV genotype-1, non-

cirrhotic subjects

• Subjects were administered ABT-450/r QD +

ABT-333 BID + weight based RBV (1000 - 1200

mg total daily dose administered twice daily) ‒ Two different doses of ABT-450/r were evaluated

in treatment-naïve subjects; one dose was

evaluated in treatment experienced subjects

• Treatment duration was 12 weeks



HCV Patients: Results

*6 were null responders and 11 were partial responders


Treatment Naive Previous Non-

Responders*

ABT-450/r 250/100

mg + ABT-333 400

mg + RBV

(n=19)

ABT-450/r 150/100

mg + ABT-333 400

mg + RBV

(n=14)

ABT-450/r 150/100

mg + ABT-333 400

mg + RBV

(n=17)

Male. n (%) 10 (52.6) 14 (100) 11 (64.7)

White, n (%) 15 (78.9) 12 (85.7) 13 (76.5)

Age, Years, Mean SD 53.6 9.78 50.9 10.45 52.3 9.03

BMI, kg/m2, Mean SD 27.3 3.84 24.6 3.08 28.3 5.11

HCV Genotype 1a, n (%) 17 (89.5) 11 (78.6) 16 (94.1)

IL28B CC Genotype, n (%) 10 (52.6) 5 (35.7) 0

Baseline HCV RNA, log10

IU/mL, Mean SD

6.25 0.80 6.44 (1.15) 6.93 0.47

Baseline Demographics


HCV Patients: Results (cont)

a1 subject discontinued due to ALT and AST; b1 subject discontinued due to failed compliance; c6 subjects had viral breakthrough; d3 subjects relapsed; e3/6 null responders and 5/11 partial

responders achieved SVR12


Treatment Naive Previous Non-

Responders

ABT-450/r 250/100

mg + ABT-333 400

mg + RBV

(n=19)

ABT-450/r 150/100

mg + ABT-333 400

mg + RBV

(n=14)

ABT-450/r 150/100

mg + ABT-333 400

mg + RBV

(n=17)

RVR: HCV RNA

<25 IU/mL at wk 4, n (%) 19 (100)a 13 (92.9)b 15 (88.2)

SVR4: HCV RNA

<25 IU/mL 4 wks after

end of treatment, n (%)

18 (94.7) 13 (92.9) 8 (47.1)c,d

SVR12: HCV RNA

<25 IU/mL 12 wks after

end of treatment, n (%)

18 (94.7) 13 (92.9) 8 (47.1)e

Virologic Results


HCV Patients: Results (cont)


• Virologic responses appear to be independent of

ABT-450/r dose and IL28B genotype in

treatment-naïve subjects

• There were no deaths or serious AEs

– The most common AEs were fatigue (42%),

nausea (22%), and headache (20%)

– Most AEs were mild or moderate; 4 subjects

experienced severe AEs (fatigue, pain,

hyperbilirubinemia, and vomiting); none resulted

in study drug interruption or discontinuation


HCV Patients: Conclusions


• An IFN-free 12-week regimen of ABT-450/r +

ABT-333 + RBV was well tolerated and achieved

SVR12 in 93 - 95% of treatment-naïve and 47% of

previous non-responder subjects infected with HCV

genotype-1.

• ABT-450/r 250/100 mg and 150/100 mg doses show

comparable efficacy in treatment-naïve subjects.

• The difference in SVR rates observed in naïve and

previous non-responders suggest that extrapolation

of results across these populations must be done

with caution

ELECTRON: Once Daily PSI-7977 plus RBV in HCV

GT1/2/3

Gane EJ, Stedman CA, Hyland RH, Sorensen RD, Symonds WT,

Hindes RG, Berrey MM Abstract 1113, Poster Presentation


the Liver

Barcelona, Spain

April 21, 2012

Once Daily PSI-7977/RBV PegIFN in Genotype-1/2/3 HCV Patients: Objective

• PSI-7977 (now GS-7977) is a uridine nucleotide

analog NS5B polymerase inhibitor

• Objective: Additional cohorts have been enrolled

in the ELECTRON study to evaluate the efficacy

of PSI-7977/RBV PegIFN in genotype 1, 2, or

3 HCV populations historically considered

difficult-to-treat with IFN and to explore shorter

durations of therapy

Gane EJ et al. J Hepatol 2012;56(Suppl 2):S438-S439.

Once Daily PSI-7977/RBV PegIFN in Genotype-

1/2/3 HCV Patients: Methods


Study

Arm

Patient-type/

Genotype

n Treatment Regimen

6 Non-cirrhotic

treatment-naïve; G2/3

10 GS-7977 + PegIFN/RBV x 8 wks

7 Prior null responders;

G1

10 GS-7977 + RBV x 12 wks

8 Prior non-responders;

G2/3

25 GS-7977 + RBV x 12 wks

9 Non-cirrhotic

treatment-naïve; G1

25 GS-7977 + RBV x 12 wks


1/2/3 HCV Patients: Results


80%88%

11%

0

20

40

60

80

100

G2/3 naive G1 null G1 naive G2/3

experienced

Is SVR4

the

correct

End

Point

100%

8 wks 12 wks

GS-7977/Peg/RBV GS-7977/RBV

10/10 1/9 22/25 12/15

SVR4

(%)


1/2/3 HCV Patients: Results (cont)


• Overall, GS-7977 was well tolerated and

exhibited a favorable safety profile

– No patients discontinued therapy due to an AE

– The most common adverse events were fatigue,

dizziness and headache

– Two grade 3/4 laboratory abnormalities were

reported

• No patients experienced viral rebound during

treatment


1/2/3 HCV Patients: Conclusions


• Preliminary results suggest that 12 wks of

therapy with oral GS-7977/RBV may be enough

to cure hepatitis C in many treatment-naive

genotype 1 patients, including those who are

currently not candidates to receive interferon

• 8 wks of a GS-7977/PegIFN/RBV treatment

regimen appears to be effective in 100% of

genotype 2/3 patients

New

SVR4 and SVR12 with an Interferon-Free Regimen of

BI201335 and BI207127, +/- Ribavirin, in Treatment-

Naïve Patients with Chronic Genotype-1 HCV Infection:

Interim Results of Sound-C2

Zeuzem S, Soriano V, Asselah T, Bronowicki J-P, Lohse A,

Müllhaupt B, Schuchmann M, Bourliere M, Buti M, Roberts S, E.

Gane E, Stern JO, Kukolj G, Dai L, Böcher WO, Mensa FJ Abstract 101, Oral Presentation


the Liver

Barcelona, Spain

April 21, 2012

SVR4 and SVR12 with BI201335 and BI207127 in Treatment-Naïve Genotype 1 HCV Patients:

Objective

• BI201335 is an HCV protease inhibitor and

BI207127 is a non-nucleoside RNA polymerase

inhibitor

• Objective: SOUND-C2 is an open-label, randomized

phase IIb study with 5 treatment arms to evaluate

the safety and efficacy of IFN-free combination

regimens of BI201335 and BI207127 RBV for up

to 40 weeks in HCV genotype 1 treatment naive

patients

• This is an interim analysis of SVR4 and SVR12

rates Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.


Methods

• 362 treatment naïve patients (including 10% compensated cirrhotics) were randomized and treated in 5 arms:

‒ A) 120 mg QD BI2011335 (1335QD) combined with 600 mg TID BI207127 (7127TID) and RBV for 16 weeks

‒ B) 1335QD + 7127TID + RBV for 28 weeks

‒ C) 1335QD + 7127TID + RBV for 40 weeks

‒ D) 1335QD + 600 mg BID BI207127 (7127BID) + RBV for 28 weeks

‒ E) 1335 + 7127TID for 28 weeks

• Randomization was stratified by HCV subtype (1a vs. 1b) and IL28B genotype

• Pre-specified interim analysis was performed after all patients (except arm C) had reached SVR12

Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S45.


Results (cont)


39%

68%

56%61%59%

0

20

40

60

80

SVR12

(%)

16 Wk 28 Wk

40 Wk

1335QD/

7127TID

28 Wk

SVR12

1335QD/7127TID/RBV 1335QD/

7127BID/

RBV

28 Wk


Results (cont)


11%

43%47%

44%38%

57%

83%

63%

73%75%

0

20

40

60

80

100

SVR12

(%)

16 Wk 28 Wk

40 Wk

1335QD/

7127TID

28 Wk

SVR12 by HCV subtype

1335QD/7127TID/RBV 1335QD/

7127BID/

RBV

28 Wk

Genotype 1a

Genotype 1b


Results (cont)


33%

64%

52%57%57% 58%

79%

68%71%

67%

0

20

40

60

80

100

SVR12

(%)

16 Wk 28 Wk

40 Wk

1335QD/

7127TID

28 Wk

SVR12 by IL28B gene

1335QD/7127TID/RBV 1335QD/

7127BID/

RBV

28 Wk

non-CC

CC


Results (cont)


• Tested regimens were generally well tolerated

overall

– Mild skin and gastrointestinal disorders were the

most commonly reported AEs, with 1335QD +

7127BID + RBV

• Discontinuation rates due to AEs in treatment

arms A through E were 5, 13, 25, 8 and 11%,

respectively


Conclusions


• INF-free combination therapy with BI201335,

BI207127 and RBV achieved 59% SVR12 in HCV

genotype 1 treatment-naïve patients after 16 weeks

of treatment and 68% SVR12 with a lower BI207127

dose (600 mg BID) for 28 weeks of treatment

• Response rates in all treatment arms were greater in

patients with genotype 1b HCV than in those with

genotype 1a

• Response rates in all treatment arms were greater in

patients with IL28B CC than in those with IL28B

non-CC

Important Points From SOUND C2

• Largest study yet showing curability of HCV

infection without interferon

• SVR rates lower than in other recent studies

– Related to “suboptimal” regimen?

• Demonstrates importance of genotype 1 subtype

and role of host response pathways in mediating

response to IFN free regiments

– Host-virus interactions illustrated by relationship

of IL28B genotype and HCV G1 subtype

The Efficacy and Safety of the Interferon-Free

Combination of BI201335 and BI207127 in Genotype 1

HCV Patients with Cirrhosis - Interim Analysis from

SOUND-C2

Soriano V, Gane E, Angus P, Stickel F, Bronowicki J-P, Roberts S,

Manns M, Zeuzem S, Dai L, Boecher W, Stern J, Mensa F Abstract 1420, Poster Presentation


the Liver

Barcelona, Spain

April 19, 2012

Efficacy and Safety of Combination BI201335 and BI207127 in Genotype1 HCV Patients with

Cirrhosis: Objective

• Interim sub-analysis of patients with compensated

liver cirrhosis enrolled in SOUND-C2

Soriano V et al. J Hepatol 2012;56(Suppl 2):S559.


Cirrhosis: Methods

• 37 patients with biopsy or Fibroscan confirmed cirrhosis were treated in 5 arms:

‒ A) 120 mg QD BI2011335 (1335) combined with 600 mg TID BI207127 (7127TID) and RBV for 16 weeks

‒ B) 1335 + 7127TID + RBV for 28 weeks

‒ C) 1335 + 7127TID + RBV for 40 weeks

‒ D) 1335 + 600 mg BID BI207127 (7127BID) + RBV for 28 weeks

‒ E) 1335 + 7127TID for 28 weeks

• All 37 patients had compensated liver disease, 25 were genotype 1b and 30 had IL-28b genotype CT/TT

• Patients who received the same dose for 16, 28, or 40 weeks (arms A, B and C) were pooled



Cirrhosis: Results


1335QD/7127TID/RBV

(n=21)

Pooled arm A, B, & C

1335QD/7127BID/RBV

(n=13)

Arm D

1335QD/7127TID

(n=3)

Arm E

GT1a

(n=5)

GT1b

(n=16)

GT1a

(n=7)

GT1b

(n=6)

GT1a

(n=0)

GT1b

(n=3)

SVR12, n (%) 3 (60) 9 (56) 2 (29) 5 (83) 0 (0) 1 (33)

Early

Discontinuation

(DC) due to

AEs, n (%)

6 (29)

-- 1 (8)

-- 0 (0)

--

Early DC due

to rash, n (%)

5 (24)

-- 0 (0)

-- 0 (0)

--

Early DC due

to

photosensitivity

n (%)

2 (10)

-- 0 (0)

-- 0 (0)

--


Cirrhosis: Results


• Mild skin and gastrointestinal disorders were the

most commonly reported AEs

• The safety and tolerability was more favorable in

the BI207127 BID arm than in the BI207127TID

arms


Cirrhosis: Conclusions


• These SVR12 rates suggest that IFN-free

combination regimens of BI201335 and BI207127

RBV may obtain similar SVR rates to those

achieved with approved DAAs + PegIFN/RBV

regimens, but with a shorter treatment duration

Potent Viral Suppression with All-Oral Combination of

Daclatasvir (NS5A Inhibitor) and GS-7977 (NS5B

Inhibitor), +/-Ribavirin, In Treatment-Naïve Patients with

Chronic HCV GT1, 2, or 3

Sulkowski M, Gardiner D, Lawitz E, Hinestrosa F, Nelson D,

Thuluvath P, Rodriguez-Torres M, Lok A, Schwartz H,

Reddy KR, Eley T, Wind-Rotolo M, S.-P. Huang S-P, Gao M,

McPhee F, Hindes R, Symonds B, Pasquinelli C, Grasela D,

AI444040 Study Group Abstract 1422, Poster Presentation


the Liver

Barcelona, Spain

April 19, 2012

All-Oral Combination of Daclatasvir and GS-7977 in Treatment Naïve Patients with Chronic HCV

GT1, 2, or 3: Objective

• Daclatasvir (DCV; BMS-790052) is an NS5A

replication complex inhibitor and GS-7977 (PSI-

7977) is a nucleotide analog NS5B inhibitor

• Objective: Study AI444040 is designed to evaluate

the safety and efficacy of IFN-free combination

regimens of DCV and GS-7977 RBV for 24 weeks

in HCV genotype 1a/1b, 2, and 3 treatment naive

patients

Sulkowski M et al. J Hepatol 2012;56(Suppl 2):S560.


GT1, 2, or 3: Methods

• A randomized phase 2a, parallel, open-label study

• 44 noncirrhotic patients with HCV genotype 1 and 44

noncirrhotics with HCV genotype 2/3 were randomized

(1:1:1) to:

‒ GS-7977 for 7 days, then DCV + GS-7977 for 23 weeks, or

‒ DCV + GS-7977 for 24 weeks, or

‒ DCV + GS-7977 + RBV for 24 weeks

• Primary endpoint is undetectable HCV RNA at 12

weeks post-treatment; interim 4-week post-treatment

efficacy and 12-week on-treatment safety results were

presented



GT1, 2, or 3: Results


GS-7977 x 7d,

then DCV +

GS-7977

DCV +

GS-7977

DCV +

GS-7977 +

RBV

GT1

n=15

GT2/3

n=16

GT1

n=14

GT2/3

n=14

GT1

n=15

GT2/3

n=14

HCV Genotype, n (%)

1a

1b

2

3

11 (73)

4 (27)

0

0

0

0

9 (56)

7 (44)

10 (71)

4 (29)

0

0

0

0

8 (57)

6 (43)

11 (73)

4 (27)

0

0

0

0

9 (64)

5 (36)

IL28B genotype CC

(rs 12979860), n (%)

CC

CT/TT

Missing

4 (27)

11 (73)

0

8 (50)

7 (44)

1 (6)

8 (57)

6 (43)

0

5 (36)

9 (64)

0

4 (27)

10 (67)

1 (7)

7 (50)

7 (50)

0

Patients Demographics: HCV Genotype and IL28B Genotype


GT1, 2, or 3: Results (cont)


GS-7977 x 7d,

then DCV +

GS-7977 (n=31)

DCV +

GS-7977

(n=28)

DCV +

GS-7977 +

RBV (n=29)

Grade 3-4 AEs 0 4 (14) 1 (4)

Discontinuations

due to AEs

0 1 (4) 1 (4)

SAEs 2 (6) 5 (18) 3 (10)

Grade 3-4 AEs, Discontinuations due to AEs, and SAEs




GS-7977 x 7d,

then DCV +

GS-7977 (n=31)

DCV +

GS-7977

(n=28)

DCV +

GS-7977 +

RBV (n=29)

Fatigue 8 (26) 14 (50) 9 (31)

Headache 5 (16) 8 (29) 9 (31)

Nausea 5 (16) 9 (32) 8 (28)

Anxiety 3 (10) 2 (7) 4 (14)

Back pain 1 (3) 5 (18) 3 (10)

Diarrhea 3 (10) 3 (11) 3 (10)

Insomnia 2 (7) 2 (7) 5 (17)

AEs occurring in 10% of patients




GS-7977 x 7d,

then DCV +

GS-7977 (n=31)

DCV +

GS-7977

(n=28)

DCV +

GS-7977 +

RBV (n=29)

Total cholesterol

elevated

1 (3) 0 0

Fasting glucose

elevated

0 0 1 (3)

Glucose elevated 0 0 1 (4)

Anemia 0 0 6 (21)

Lymphopenia

(absolute)

0 0 1 (3)

Low phosphorus 0 1 (4) 1 (3)

Grade 3-4 Laboratory Abnormalities



*LOD=<10 IU/mL


47

87

100

87

14

93 93

86

100

20

73

100

93

100100

0

20

40

60

80

100

Wk2 Wk4 Wk12 Wk 24(EOT)

PT Wk 4(SVR4)

HCV RNA

<LOD*

(% of

Patients)

GS-7977 x 7d, then DCV + GS-7977 (n=15)

DCV + GS-7977 (n=14)

DCV + GS-7977 + RBV (n=15)

Virologic Response (<LOD)

Before and After Treatment

of HCV Genotype 1a/1b



*LLOQ=25 IU/mL


67

100 100

87

79

100

93

86

100

67

100 100

93

100100

0

20

40

60

80

100


PT Wk 4(SVR4)

HCV RNA

<LLOQ*

(% of

Patients)

GS-7977 x 7d, then DCV + GS-7977 (n=15)

DCV + GS-7977 (n=14)

DCV + GS-7977 + RBV (n=15)

Virologic Response (<LLOQ)


of HCV Genotype 1a/1b



*LOD=<10 IU/mL


31

88 8893

29

79

93 93

100

29

64

93

86

79

88

0

20

40

60

80

100


PT Wk 4(SVR4)

HCV RNA

<LOD*

(% of

Patients)

GS-7977 x 7d, then DCV + GS-7977 (n=16)

DCV + GS-7977 (n=14)

DCV + GS-7977 + RBV (n=14)

Virologic Response (<LOD)


of HCV Genotype 2/3



*LLOQ=25 IU/mL


81

100

8894

86

100

93

100 100

86

100 100

86 8688

0

20

40

60

80

100


PT Wk 4(SVR4)

HCV RNA

<LLOQ*

(% of

Patients)

GS-7977 x 7d, then DCV + GS-7977 (n=16)

DCV + GS-7977 (n=14)

DCV + GS-7977 + RBV (n=14)

Virologic Response (<LLOQ)


of HCV Genotype 2/3

All-Oral Combination of Daclatasvir and GS-7977

in Treatment Naïve Patients with Chronic HCV



0

20

40

60

80

100

Genotype 1a Genotype 1b

SVR4

(% of

Patients)

SVR4 by Genotype 1 Subtype and IL288 Genotype

CC

CT/TT

100% 100% 100% 100%


GT1, 2, or 3: Conclusions


• The all oral IFN-free regimen of DCV + GS-7977

with or without RBV for 24 wks attained SVR4 in

>95% of genotype 1, 2, or 3 infected treatment naive

patients including 100% of genotype 1 patients

treated

• The all oral, once daily, IFN-free, RBV-free of DCV +

GS-7977 attained SVR4 100% of genotype 1 and

>90% of genotype 2 and 3 treatment naive patients

• DCV + GS-7977 achieved SVR independent of

IL288 genotype or HCV subtype


GT1, 2, or 3: Conclusions (cont)


• RBV contributed AEs but had no effect on virologic

response

• DCV + GS-7977 was generally well tolerated based on

the interim 12 week on-treatment data

• DCV + GS-7977 may represent a significant advance in

the treatment of HCV

– More generally, 2 potent drugs with at least one

component also featuring a high barrier to resistance

may represent an important new paradigm; need studies

in nonresponders, cirrhotics

• Further follow-up and additional studies in progress

Dual Oral Therapy with the NS5A Inhibitor Daclatasvir

(BMS-790052) and NS3 Protease Inhibitor Asunaprevir

(BMS-650032) in HCV Genotype 1B-Infected Null

Responders or Ineligible/Intolerant to

Peginterferon/Ribavirin

Suzuki F, Ikeda K, Toyota J, Karino Y, Ohmura T, Chayama K,

Takahashi S, Kawakami Y, Ishikawa H, Watanabe H, Hu W,

McPhee F, Hughes E, Kumada H Abstract 14, Oral Presentation


the Liver

Barcelona, Spain

April 19, 2012

Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or

Ineligible/Intolerant: Objective

• Daclatasvir (DCV; BMS-790052) is a highly selective

NS5A replication complex inhibitor and asunaprevir

(BMS-650032) is a selective inhibitor of HCV NS3

protease

• Objective: To evaluate the safety and efficacy of

dual therapy with daclatasvir and asunaprevir, two

direct-acting antivirals, in HCV genotype 1B patients with

intolerance or prior null response to PegIFN/RBV

Suzuki F et al. J Hepatol 2012;56(Suppl 2):S7-S8.


Ineligible/Intolerant: Methods

• Open-label study of 21 null responders (<2 log10 HCV

RNA after 12 weeks of Peg-IFN/RBV, group A) and

22 patients ineligible for IFN-containing regimens for

medical reasons or who discontinued Peg-IFN/RBV

after <12 weeks due to intolerance (group B)

• Patients received daclatasvir 60 mg QD and

asunaprevir 200 mg BID (initially 600 mg BID in 10/21

subjects in group A) for 24 weeks

• Addition of Peg-IFN was permitted for Group A

patients with virologic failure



Ineligible/Intolerant: Results


Null Responders

(Group A, N=21)

Ineligible/

Intolerant

(Group B, N=22)

IL28B genotype CC,

n/N (%)

3/21 (14.3) 16/22 (72.7)

HCV undetectable wk 4 (RVR),

n/N (%)

11/21 (52.4) 19/22 (86.4)

HCV undetectable wk 12 (cEVR),

n/N (%)

19/21 (90.5) 20/22 (90.9)

HCV undetectable wk 24 (EOT),

n/N (%)

18/32 (85.7) 16/22 (72.7)

HCV below LLOQ post-treatment

week 12 (SVR12), n/N (%)

19/21 (90.5) 14/22 (63.6)

Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or Ineligible/Intolerant: Results (cont)


• All 43 enrolled patients were Japanese with HCV genotype 1b

• Baseline characteristics were similar other than a higher

proportion of IL28B genotype CC in group B vs. A (73% vs.

14%)

• 3 patients discontinued prematurely for AEs, 1 for lack of

efficacy (group A) and 2 per patient request

• 3 patients had viral breakthrough, 1 before wk 12; HCV

variants associated with asunaprevir and daclatasvir

resistance were identified

• Serious AEs included 1 patient with hyperbilirubinemia and

gastroenteritis, 3 with pyrexia, and 1 hypochondriasis

Daclatasvir and Asunaprevir Dual Therapy in HCV Genotype 1B Null Responders or Ineligible/Intolerant: Conclusions


• The dual oral DAA combination of daclatasvir

and asunaprevir, without PegIFN/RBV, may offer

a needed therapeutic alternative to

PegIFN/RBV-containing regimens for many

patients, including some difficult-to-treat groups

• Difference between genotype 1a and 1b shown

in earlier study of this regimen emphasizes

importance of G1 subtype, at least with

regimens lacking a component with high

resistance barrier (or, perhaps, lacking RBV)

Confirmation that Quadruple Therapy with Daclatasvir

(NS5A Inhibitor), Asunaprevir (NS3 Inhibitor) and

Peginterferon/Ribavirin Results in High Rate of SVR4 in

HCV Genotype 1 Null Responders

Lok A, Gardiner D, Hézode C, Lawitz E, Bourlière M, Everson G,

Marcellin P, Rodriguez-Torres M, Pol S, Serfaty L, Eley T, Huang

S-P, Wind-Rotolo M, McPhee F, Grasela D,

Pasquinelli C Abstract 1415, Poster Presentation


the Liver

Barcelona, Spain

April 19, 2012

Daclatasvir, Asunaprevir and Peg-IFN/RBV in HCV

Genotype 1 Null Responders: Objective

• Daclatasvir is an NS5A inhibitor; asunaprevir is an

NS3 inhibitor

• Objective: Using a lower asunaprevir dose in a

larger null-responder population, to confirm results

of a preliminary study that found combination

therapy with declatasvir (DCV), asunaprevir (ASV),

Peg-IFN, and RBV resulted in a 90% SVR rate in

HCV patients with a prior null-response to Peg-

IFN/RBV

Lok A et al. J Hepatol 2012;56(Suppl 2):S557.


Genotype 1 Null Responders: Methods

• Randomized, open label, phase 2a study in non-

cirrhotic HCV null-responders to Peg-IFN/RBV

• Patients received ASV 200 mg QD (n=21) or BID

(n=20), each combined with DCV 60 mg QD and

Peg-IFN/RBV x 24 weeks



Genotype 1 Null Responders: Results

• Patients had multiple negative predictors of SVR to

Peg-IFN/RBV therapy:

‒ 88% were HCV GT1a

‒ 61% had baseline HCV RNA 106 IU/mL

‒ 100% were IL28B genotype CT/TT

• AEs and laboratory abnormalities were typical of

Peg-IFN/RBV; none led to treatment discontinuation

‒ Most common AEs were headache, asthenia, diarrhea,

irritability, and fatigue

‒ Most common grade 3/4 laboratory abnormalities were

neutropenia (11 patients), decreased white blood cells (6),

lymphopenia (6), and low phosphorus (2)





85%90%

95%

75%

95%100%

95%

71%

0

20

40

60

80

100

120

Week 4 Week 12 Week 24

(EOT)

SVR4

Patients

<LOD

(%)

DCV + ASV 200 mg BID + Peg-IFN/RBV (n=20)

DCV + ASV 200 mg QD + Peg-IFN/RBV (n=21)




0

20

40

60

80

100

Week 4 Week 12 Week 24

(EOT)

SVR4

Patients

<LLOQ

(%)

DCV + ASV 200 mg BID + Peg-IFN/RBV (n=20)

DCV + ASV 200 mg QD + Peg-IFN/RBV (n=21)

95% 95% 100% 100% 100% 100% 95% 100%


Genotype 1 Null Responders: Conclusions


• The expansion cohort confirmed that the

quadruple combination of DCV, ASV, and Peg-

IFN/RBV provided rapid viral suppression with

SVR4 rates over 90% in this difficult-to-treat

patient population

Peginterferon Lambda-1a (Lambda) Compared to

Peginterferon Alfa-2A (ALFA) in Treatment-Naïve

Patients with HCV Genotypes (G) 2 or 3: First SVR 24

Results from EMERGE Phase IIB

Zeuzem S, Arora S, Bacon B, Box T, Charlton M, Diago M, Dieterich D, Mur RE,

Everson G, Fallon M, Ferenci P, Flisiak R, George J, Ghalib R, Gitlin N, Gladysz

A, Gordon S, Greenbloom S, Hassanein T, Jacobson I, Jeffers L, Kowdley K,

Lawitz E, Lee SS, Leggett B, Lueth S, Nelson D, Pockros P,

Rodriguez-Torres M, Rustgi V, Serfaty L, Sherman M, Shiffman M, Sola R,

Sulkowski M, Vargas H, Vierling J, Yoffe B, Ishak L, Fontana D, Xu D, Gray T,

Horga A, Hillson J, Lopez-Talavera JC, Muir A, EMERGE Study Group



the Liver

Barcelona, Spain

April 19, 2012

PegIFN lambda-1A Compared to PegIFN alfa-2a in Treatment Naïve HCV Genotype 2 or 3 Patients:

Objective

• PegIFN lambda exerts antiviral effects through a

unique receptor with limited distribution outside the

liver and is expected to have an improved tolerability

profile vs. PegIFN alfa

• Objective: To assess safety and efficacy of PegIFN

lambda-1a/RBV in treatment-naïve HCV genotype 2

and genotype 3 patients compared to PegIFN alfa-

2a/RBV

Zeuzem S et al. J Hepatol 2012;56(Suppl 2):S5-S6.

TMC435 in HCV Genotype 1 Patients who Have Failed

Previous Pegylated Interferon/Ribavirin Treatment: Final

SVR 24 Results of the ASPIRE Trial

Zeuzem S, Berg T, Gane E, Ferenci P, Foster GR, Fried MW,

Hezode C, Hirschfield G, Jacobson I, Nikitin I, Pockros P,

Poordad F, Lenz O, Peeters M, V. Sekar V, De Smedt G,

Beumont-Mauviel M



the Liver

Barcelona, Spain

April 19, 2012

TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Objective

• TMC435 is an oral, once-daily, HCV NS3/4A

protease inhibitor

• Objective: ASPIRE is an international Phase IIb,

randomized, double-blind, placebo-controlled trial

investigating the efficacy, tolerability, safety, and

pharmacokinetics of TMC435 administered with

PegIFN/RBV


TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Methods

• Patients were chronically-infected with HCV genotype

1, with documented evidence of null-response (<2

log10 reduction wk 12), partial response ( 2 log10

reduction wk 12; detectable end-of-treatment) or

relapse (undetectable end-of-treatment; detectable

within 24 wks post-treatment) following 1 course of

PegIFN/RBV therapy

• Patients were randomized to 1 of 7 treatment arms:

• TMC435 (100 or 150 mg once-daily) for 12, 24, or 48 wks

in combination with 48 wks of PegIFN/RBV, or

• Placebo with PegINF/RBV for 48 wks


TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Results

(cont)


38

56

44

53

41

59

19

70

48

55

65

75

86

9

89 89

77 77

89 89

37

0

20

40

60

80

100

TMC12/

PR48

100 mg

TMC24/

PR48

100 mg

TMC48/

PR48

100 mg

TMC12/

PR48

150 mg

TMC24/

PR48

150 mg

TMC48/

PR48

150 mg

PBO48/

PR48

SVR24

Patients

(%)

Prior Null Responder Prior Partial Responder Prior Relapser

TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment: Results

(cont)


• Of 462 patients enrolled:

– 19% had Metavir score F3 and 18% F4

– 41% were infected with genotype 1a and 58% 1b

• Discontinuation due to viral breakthrough or lack of on-

treatment response was 9 - 17% in TMC435-treated

groups compared to 53% for the control group

• Viral relapse occurred in 6 - 18% of TMC435-treated

patients compared to 44% in the control group

• Incidence of AEs leading to treatment discontinuation

and serious AEs was similar across all groups

– Mild, transient, asymptomatic bilirubin increases were observed

with TMC435, with no significant differences between 100 mg

and 150 mg doses

TMC435 in HCV Genotype 1 Patients who Have Failed Previous PegIFN/RBV Treatment:

Conclusions


• Patients who failed previous PegIFN/RBV

treatment exhibited significantly higher SVR24

rates following treatment with TMC435 plus

PegIFN/RBV compared with placebo, including

difficult-to-treat prior null-responders with

cirrhosis

• TMC435 was well tolerated in this population


Conclusions (cont)

• Promising studies of IFN-free regimens with high

levels of efficacy and short durations (12-24 weeks)

• Host-virus interactions are important with some

regimens:

– Genotype 1a, IL28B CT/TT, null response to earlier

PR therapy adversely impact response with

regimens that lack “optimal” potency and/or high

resistance barrier

– Will “optimized” regimens overcome these factors?


Conclusions

• No data were presented which specifically

addressed response rates in black patients; need

much more data on cirrhotics

• Most studies are too preliminary for definitive

conclusions regarding safety; encouraging signal of

no unusual safety issues to date

• The future is unfolding rapidly – optimal decision-

making requires knowledge of current developments

hepatitis c: emerging therapies

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