Emerging Therapies for HCV: Highlights from AASLD 2012 ... · November 9 - 13, 2012 Boston, MA Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A; *Soriano V et al, Abstract

Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 1)

Emerging Therapies for HCV: Highlights from AASLD 2012 (Part 1)

Robert S. Brown, Jr., MD, MPH Frank Cardile Professor of Medicine Chief, Center for Liver Disease and Transplantation Columbia University College of Physicians & Surgeons New York Presbyterian New York, NY

Part 1. An overview of selected all oral HCV direct acting antiviral (DAA) therapy presentations from:

http://www.aasld.org/lm2012

Program Disclosure

• This activity has been planned and implemented in

accordance with the Essential Areas and Policies of the

Accreditation Council for Continuing Medical Education

(ACCME) through the sponsorship of Annenberg Center for

Health Sciences at Eisenhower and the Chronic Liver Disease

Foundation. Annenberg Center for Health Sciences at

Eisenhower is accredited by the ACCME to provide continuing

medical education for physicians.

• This program is supported by educational grants from

Janssen and Vertex Pharmaceuticals.

Educational Objectives

• Describe development goals for future therapies for the

treatment of chronic hepatitis C

• Assess potential efficacy and safety of new orally

effective compounds currently under investigation for the

treatment of chronic hepatitis C

• Recognize how new compounds might fit into the future

treatment armamentarium for chronic hepatitis C

Goals for Hepatitis C Therapy

• 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

Selected Oral Directing Acting Antivirals for the

Treatment of Chronic Hepatitis C, 2012

Compound Sponsor Activity

ABT-267 Abbott NS5A inhibitor

ABT-333 Abbott Non-nucleoside NS5B

polymerase inhibitor

ABT-450 Abbott NS3/4A protease

inhibitor

Faldaprevir

(BI201335)

Boehringer Ingelheim NS3/4A protease

inhibitor

BI207127 Boehringer Ingelheim Non-nucleoside NS5B


Selected Oral Directing Acting Antivirals for the

Treatment of Chronic Hepatitis C, 2012 (cont)

Compound Sponsor Activity

Asunaprevir

(BMS-650032)

Bristol-Myers Squibb NS3 protease inhibitor

Daclatasvir

(BMS-790052)

Bristol-Myers Squibb NS5A replication

complex inhibitor

BMS-791325 Bristol-Myers Squibb Non-nucleoside NS5B


Sofosbuvir

(GS-7977)

Gilead Uridine nucleotide

analog NS5B


GS-5885 Gilead NS5A protein inhibitor

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

Interferon (IFN)-Free Combination Treatment with

the HCV NS3/4A Protease Inhibitor BI 201335 and

the Non-Nucleoside NS5B Inhibitor BI 207127 ±

Ribavirin (R): Final Results of SOUND-C2 and

Predictors of Response

Zeuzem S, Soriano V, Asselah T, Bronowicki J-P, Lohse AW, Mullhaupt B,

Schuchmann M, Bourliere M, Buti M, Roberts SK, Gane EJ, Stern JO,

Vinisko R, Herichova I, Boecher WO, Mensa FJ

Abstract 232, AASLD 2012

Emerging Therapies for HCV: Highlights from AASLD 2012

November 9 - 13, 2012 Boston, MA

Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A; *Soriano V et al, Abstract 84, AASLD 2012

• Five arm study that evaluated different doses and durations in

regimens with faldaprevir (PI) and BI207127 (non-nuc) with or

without RBV

– Durations: 16, 28 or 40 weeks

– BID vs TID

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

– 9% of patients had cirrhosis

• SVR12 ranged between 52% to 69% in RBV-containing arms and

39% without RBV

– SVR in cirrhotics is 54%*

• IL28B CC, genotype 1b and female gender were favorably

associated with SVR12

SOUND-C2 Trial Update: BI 201335 + BI 207127 RBV

Once Daily Sofosbuvir (GS-7977) Plus Ribavirin in

Patients with HCV Genotypes 1, 2, and 3:

The ELECTRON Trial

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

Symonds WT, Hindes R, Berrey MM

Abstract 229, AASLD 2012



ELECTRON Trial

Objective

• To evaluate sofosbuvir (SOF; formerly GS-7977), a uridine nucleotide analog, plus ribavirin (RBV) in additional ELECTRON study arms: – SOF + RBV in treatment-naïve genotype 1 patients

– SOF + RBV in null responder genotype 1 patients

– SOF + RBV in treatment experienced (Prior null response, breakthrough, or relapse) in genotype 2/3 patients

– To determine feasibility of shorter duration or reduced dose of RBV in treatment naive genotype 2/3 patients

• To evaluate the efficacy and safety of adding GS-5885, an NS5A inhibitor, to SOF + RBV in treatment naïve and null responder genotype 1 patients

Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A Press release. November 10, 2012. Gilead Sciences, Inc., Foster City, CA. Available at http://www.gilead.com/pr_1757156.

http://www.gilead.com/pr_1757156

ELECTRON Trial Update: Sofosbuvir (GS-7997) +

Ribavirin in Genotypes 2 and 3 HCV

Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A Press release. November 10, 2012. Gilead Sciences, Inc., Foster City, CA. Available at http://www.gilead.com/pr_1757156.

Treatment Population Results

SOF + RBV, 12 wks GT 2/3 Treatment-

experienced

68% (17/25) SVR12

SOF + RBV, 12 wks GT 2/3 Treatment-naïve 100% (11/11) SVR24

SOF + RBV, 8 wks GT 2/3 Treatment-naïve

64% (16/25) SVR12

SOF + RBV (800 mg),

12 wks

GT 2/3 Treatment-naïve

60% (6/10) SVR8

http://www.gilead.com/pr_1757156

ELECTRON Trial Update: Sofosbuvir + RBV vs. SOF +

GS-5885 + RBV in Genotype 1 HCV

*Includes one patient who stopped all treatment for SAE at week 8 Data collection ongoing Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A

SOF + RBV SOF + GS-5885 + RBV

Treatment-

Naïve

(n=25)

Null

Responder

(n=10)

Treatment-

Naïve

(n=25)

Null

Responder

(n=9)

Week 1 8/25 (32) 1/10 (10) 11/25 (44) 0/9 (0)

Week 2 17/25 (68) 7/10 (70) 22/25 (88) 4/9 (44)

Week 4 25/25 (100) 10/10 (100) 25/25 (100) 8/9 (89)

EOT (Week 12) 25/25 (100) 10/10 (100) 25/25 (100) 9/9 (100)

SVR4 22/25 (88) 1/10 (10) 25/25 (100)* 3/3 (100)

SVR12 21/25 (84) 1/10 (10) --- ---

Patients with HCV RNA <LOD over time, n/N (%)

ELECTRON Trial Summary: Genotype 1 HCV

Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A

• SOF + RBV for 12 weeks provided SVR12 in 84% of

treatment-naïve, but only in 10% of null responders

• Addition of GS-5885 increased efficacy of SOF +

RBV

– 100% SVR4 in treatment-naïve patients

– 3/3 SVR4 in null responders

– No additional safety/tolerability issues detected

ELECTRON Trial Summary: Genotype 2 or 3 HCV

Gane EJ et al. Hepatology 2012; 56(Suppl S1):306A-307A

• SOF + RBV for 12 weeks appears to be a safe and

effective regimen for both treatment-naïve and

previously treated patients

– Durations of less than 12 weeks or reduced RBV

dose may adversely impact treatment efficacy

High Efficacy Of GS-7977 (SOF) In Combination

With Low or Full dose Ribavirin for 24 weeks In

Difficult To Treat HCV Infected Genotype 1 Patients :

Interim Analysis From The SPARE Trial

Osinusi A, Heytens L, Lee Y-J, Bon D, Shivakumar B, Nelson A, Meissner EG,

Kohli A, Barrett L, Proschan M, Silk R, Kwan R, Herrmann E, Sneller M,

Teferi G, Talwani R, Symonds WT, Polis MA, Masur H, McHutchison JG,

Fauci AS, Kottilil S

Abstract LB-4, AASLD 2012



SOF in Combination with Low or Full Dose RBV in

Difficult to Treat Genotype 1 HCV Patients

Osinusi A et al. Abstract LB-4. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

SOF + RBV 1000-1200 mg

N=10

SOF + RBV 1000-1200 mg

N=25

SOF + RBV 600 mg

N=25

Study Design • Sixty HCV genotype 1, treatment-naive subjects • Part 1: Stages 0 - 2 fibrosis • Part 2: All stages (including Child Pugh Class A)

24 weeks

Part 1 Part 2

SVR 12

SVR 12

SVR 12




Baseline Demographics SOF +

Full dose

RBV

(N=10)

SOF +

Full dose RBV

(N=25)

SOF +

Low dose RBV

(N=25)

Median age (range) 54 (30-65) 54 (30-65) 55 (26-78)

Male sex (%) 4 (40%) 20 (80%) 14 (56%)

Genotype 1a (%) 6 (60%) 20 (80%) 16 (64%)

African American (%) 9 (90%) 18 (72%) 23 (92%)

Median BMI (range) 26 (22-43) 28 (22-44) 30 (19-47)

IL28B CT/TT (%) 6 (67%) 21 (84%) 21 (84%)

Median HCV RNA log

(IQR)

6.85

(5.80-7.21)

6.16

(5.37-6.41)

6.05

(5.49-6.36)

Advanced fibrosis (%) 0 6 (24%) 7 (28%)




Treatment Response: Full dose RBV (Part 1; N=10)

90%90%90%90%90%

0

20

40

60

80

100

Week 4 Week 12 ETR SVR4 SVR12

ITT HCV RNA

<LLOQ (%)

• mITT: 100% SVR12 (1 drop out at week 3)




Treatment Response: Part 2

72%

96%96%96%

56%

88%88%96%

0

20

40

60

80

100

Week 4 Week 12 ETR SVR4

ITT HCV RNA

<LLOQ (%)

• mITT: 75 % SVR4 for full dose RBV; 64% for low dose RBV

Full dose RBV (N=25); 1 drop out at wk 3

Low dose RBV (N=25) 3 drop outs by wk 8




Conclusions:

• In this inner city population of HCV genotype 1

treatment-naïve patients, SOF + RBV

administered for 24 weeks resulted in:

– Full dose RBV: SVR4 of 77%

– Low dose RBV: SVR4 of 56%

• There were no safety signals or drug-related

discontinuations in this study

High Rate of Sustained Virologic Response with the All-Oral Combination of Daclatasvir (NS5A Inhibitor) Plus Sofosbuvir (Nucleotide NS5B Inhibitor), With or

Without Ribavirin, in Treatment-Naïve Patients Chronically Infected With HCV Genotype 1, 2, or 3

Sulkowski MS, Gardiner DF, Rodriguez-Torres M, Reddy KR, Hassanein T,

Jacobson IM, Lawitz E, Lok AS, Hinestrosa F, Thuluvath PJ, Schwartz H,

Nelson DR, Eley T, Wind-Rotolo M, Huang S-P, Gao M, McPhee F, Sherman

D, Hindes R, Symonds WT, Pasquinelli C, Grasela DM




n = 41

n = 15

n = 14

SVR12 Week 24 SVR24

Follow-up

n = 41

n = 15

Follow-up

Follow-up

Follow-Up

SVR4 Week 12

Follow-Up

Group C: DCV 60 mg QD + SOF 400 mg QD

Group E: DCV 60 mg QD + SOF 400 mg QD + RBV

Group A: SOF 400 mg QD x 7d, then DCV 60 mg QD + SOF 400 mg QD

Group G: DCV 60 mg QD + SOF 400 mg QD

Group H: DCV 60 mg QD + SOF 400 mg QD + RBV

SVR4 SVR48

SVR48

Study Design: GT 1a/1b

Sulkowski MS et al. Abstract LB-2. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

20

SVR4 Week 4 SVR12

n =

EOT

15 14 15

SVR24

C: DCV + SOF

A: SOF LI + DCV

E: DCV + SOF

+ RBV

100

15 14 15 15 14 15 15 14 15 15 14 15

100 100 100 100 100 100 100 100 100 100 100 100 100

93

HC

V R

NA

< L

LO

Q (%

pa

tie

nts

)

Virologic Response is Maintained at PT Week 24

(GT1a/1b; 24-Week Treatment Groups)


SVR4

HC

V R

NA

< L

LO

Q

(% p

ati

en

ts)

Week 4

n =

EOT

G: DCV + SOF (12-wk)

H: DCV + SOF + RBV (12-wk)

100 95 100 100 98 95

41 41 41 41 41 41

Virologic Response During and After Treatment:

12 Week Treatment Groups (GT 1a/1b)


Virologic Response is Maintained at PT Week 24

(GT 2 or 3; 24-Week Treatment Groups)


10094

88 88 88

100 100 100 100 100100 100

86 8693

0

20

40

60

80

100

120

Week 4 EOT SVR4 SVR12 SVR24

HCV RNA <LLOQ

(% patients)

SOF LI + DCV DCV + SOF DCV + SOF + RBV

16 14 14 16 14 14 16 14 14 16 14 14 16 14 14

All-Oral Combination of Daclatasvir Plus Sofosbuvir

Ribavirin in Treatment Naïve HCV GT 1, 2, or 3


Conclusions:

• DCV + SOF with or without RBV achieved SVR

in 93% of patients with HCV genotype 1, 2, or 3

• HCV genotype 2 or 3 (N=44)

– 24-week duration: SVR24=93% of patients

• HCV genotype 1 (N=126)

– 12-week duration: SVR4=96%

– 24-week duration: SVR24=98%

An Interferon-Free, Ribavirin-Free 12-Week Regimen of Daclatasvir (DCV), Asunaprevir (ASV), and BMS-

791325 Yielded SVR4 of 94% in Treatment-Naïve Patients with Genotype (GT) 1 Chronic Hepatitis C

Virus (HCV) Infection

Everson GT, Sims KD, Rodriguez-Torres M, Hezode C, Lawitz E, Bourliere M,

Loustaud-Ratti V, Rustgi VK, Schwartz H, Tatum HA, Marcellin P, Pol S,

Thuluvath PJ, Eley T, Wang X, Huang SP, McPhee F, Wind-Rotolo M,

Chung E, Pasquinelli C, Grasela DM, Gardiner DF




• In pilot studies, 24 weeks of DCV + ASV was effective in

prior null responders with HCV GT 1b infection

• In this Phase 2a study with DCV + ASV + BMS-791325,

objective was to

– Enhance virologic responses

– Improve efficacy in GT 1a

– Maintain tolerability

– Shorten treatment duration to 12 weeks

• DCV is an NS5A replication complex inhibitor, ASV is an

NS3 protease inhibitor, and BMS-791325 is a selective

non-nucleoside NS5B polymerase inhibitor

IFN-Free, RBV-Free 12-Week Regimen of Daclatasvir,

Asunaprevir, and BMS-791325 in Treatment-Naive

Genotype 1 HCV

94%**

SV

R(%

)

**One lost to follow up



Genotype 1 HCV

Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012



Genotype 1 HCV: Preliminary Results

Everson GT et al. Abstract LB-3. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012

Conclusions

•DCV + ASV + BMS-791325 resulted in high rates

of SVR after both 12 and 24 weeks of treatment

•Regimen was generally well tolerated

•There was no viral breakthrough and no post

treatment relapse to date

A 12-Week Interferon-free Treatment Regimen with

ABT-450/r, ABT-267, ABT-333 and Ribavirin

Achieves SVR12 Rates (Observed Data) of 99% in

Treatment-Naïve Patients and 93% in Prior Null

Responders with HCV Genotype1 Infection

Kowdley KV, Lawitz E, Poordad F, Cohen DE, Nelson DR, Zeuzem S,

Everson GT, Kwo PY, Foster GR, Sulkowski MS, Xie W, Pilot-Matias T,

Liossis G, Larsen LM, Khatri A, Podsadecki TJ, Bernstein B




ABT-450/r, ABT-267, ABT-333 and RBV in Treatment

Naïve and Prior Null Responders with Genotype 1 HCV

Objective

• To assess efficacy and safety of several interferon free

regimens of ABT-450/r with ABT-267 and/or ABT-333

ribavirin (RBV)

– ABT-450 is an HCV NS3/4 protease inhibitor that is co-

administered with ritonavir (ABT-450/r) and dosed once daily

– ABT-267 is an NS5A inhibitor that is dosed once daily

– ABT-333 is a non-nucleoside polymerase inhibitor dosed twice

daily

Kowdley KV et al. Abstract LB-1. Presented at The Liver Meeting 2012, Boston, MA, November 9-13, 2012




93.3%88.9%

97.5%

87.3%89.9%85.4%87.5%

0

20

40

60

80

100

ITT SVR12

(%)

ABT-450

ABT-333 RBV

ABT-450 ABT-267

RBV

ABT-450 ABT-267 ABT-333

ABT-450 ABT-267 ABT-333

RBV

ABT-450 ABT-267 ABT-333

RBV

ABT-450 ABT-267

RBV

ABT-450 ABT-267 ABT-333

RBV

8 wks 12 wks 12 wks

Treatment Naïve Prior Null Responder

n=80 n=79 n=79 n=79 n=45 n=45 n=41

SVR12 Rates (ITT) for 8- and 12-week Arms



Safety

•All DAA combinations studied were well tolerated

through 8-12 weeks of treatment

– Fatigue, headache, insomnia, and nausea were seen

most frequently

– Transient asymptomatic elevation of indirect bilirubin

was seen, consistent with the known effect of ABT-

450 on the bilirubin transporter OATP1B1

– 1% of patients discontinued due to adverse events




Conclusions

• The 12-week 3 DAA + RBV regimens showed the

greatest efficacy in both treatment-naive and null

responder populations

• All DAA combinations studied were well tolerated

through 8 - 12 weeks of treatment

• Phase 3 studies with the 3 DAA combination (with

and without RBV) recently initiated

Emerging Therapies for HCV: Highlights from

AASLD 2012

Summary

• Compared to current treatment regimens for chronic

hepatitis C, therapies currently under investigation

offer:

– Improved efficacy

– Oral effectiveness (IFN free)

– Shorter treatment durations

• While most studies are too preliminary for definitive

conclusions regarding safety, no unusual safety

issues have been identified to date

Emerging Therapies for HCV: Highlights from

AASLD 2012

Summary

• As with current IFN-containing treatment regimens,

host (IL28B genotype) and virus (genotype 1a/1b)

interactions influence treatment outcomes with

certain DAA combinations

• Additional data are needed in difficult-to-treat patient

groups (Blacks, cirrhotics, previously treated patients)

• To treat now or to wait ‒ optimal decision-making

requires knowledge of current developments

Documents

Emerging Therapies for HCV: Highlights from AASLD 2012 ... · November 9 - 13, 2012 Boston, MA Zeuzem S et al. Hepatology 2012; 56(Suppl S1):308A-309A; *Soriano V et al, Abstract