New developments in HCV research and their implications ...Highlights From AASLD 2010 SPRINT-2: Response Rates According to Race 0 20 40 40 60 80 80 100 100) SVR Relapse 4-wk PR +

New developments in HCV research and their implications

for front-line practice

Dr. Curtis Cooper

Associate Professor, University of Ottawa

Director, Ottawa Hospital Viral Hepatitis Program

June 17, 2013

New developments in HCV research and their

implications for front-line practice

Curtis Cooper, MD, FRCPC

Associate Professor-University of Ottawa

The Ottawa Hospital- Infections Diseases

Viral Hepatitis Program- Director

Disclosures Industry

Investigator: Merck, Vertex, Roche, BI, Janssen, GS, BMS, ABT

Consultant /Advisor: Merck, Vertex, Roche, BI, GS

Speaker: Merck, Roche, BI, BMS

Government

CADTH

OHTN

CIHR

PCIRN

Health Canada

Ontario MOH

Overview

Overview of HCV and

Current Standard of Care

Future Therapies

HIV-HCV co-infection

issues

New Treatment Guidelines

Sexual Transmission of HCV

Effective Service Delivery

Models

Other relevant topics

Therapies for Hepatitis C Virus

PEG-Interferon α / Ribavirin

Duration of Tx / RGT

Definition of Therapeutic

Success

Plasma HCV RNA undetectable

6 months post therapy

(Sustained Virologic

Response=Cure)

hypervariable region

capsid envelope protein

Protease / Helicase

RNA-dependent RNA Polymerase

c22

5’

core

E1 E2 NS2

NS3

33c

NS4

c-100

NS5a / NS5b

3’

Direct Acting Antivirals

Direct Acting Antiviral Drug (DAA) Combinations

clinicaloptions.com/hepatitis

Highlights From AASLD 2010

Boceprevir and Telaprevir

Boceprevir, a potent inhibitor of HCV NS3 protease

Telaprevir, a potent inhibitor of HCV NS3/4A protease

Dosed in combination with standard-of-care peginterferon alfa-2/ ribavirin

Key Phase III Studies

Boceprevir

– SPRINT-2: naive GT1 patients

– RESPOND-2: nonresponder GT1 patients

Telaprevir

– ADVANCE: naive GT1 patients

– ILLUMINATE: response-guided therapy in naive GT1 patients



SPRINT-2: Response Rates According to

Race

0

20

40

60

80

100

Pati

en

ts (

%)

SVR Relapse

4-wk PR + 44 weeks BOC + PR 4-wk PR + response-guided BOC + PR 48-wk PR

67 68

40

8

23

9

0

20

40

60

80

100

Pati

en

ts (

%)

SVR Relapse

42

53

23

17 14 12

Nonblack Patients Black Patients

P < .0001 P = .044

P = .004

Poordad F, et al. AASLD 2010. Abstract LB-4.

n = 211 213 125 21 18 37 22 29 12 3 6 2



RESPOND-2: SVR Rates According to

Treatment Arm and Prior Response

0

20

40

60

80

100

Overall

SV

R (

%)

4-wk PR + 44-wk BOC + PR (n = 161)

59*

Previous Nonresponders

Previous Relapsers

48-wk PR (n = 80)

4-wk PR + response-guided BOC + PR (n = 162)

66

21

40

52

7

75

29

69

P < .0001 vs control

(both arms)

Bacon BR, et al. AASLD 2010. Abstract 216.

95/

162 107/161

17/80

23/57

30/58 2/29

72/105

77/103

15/51

•Overall RR

•RGT 15%

•FD 12%

•Control 32%



ADVANCE: Overall SVR and Relapse

Rates

0

20

40

60

80

100

Pati

en

ts (

%) 69

SVR

75

44

P < .0001 for both treatment arms vs control

12-wk TVR + PR + 12/36-wk PR (n = 363)

48-wk PR (n = 361)

8-wk TVR + PR + 16/40-wk PR (n = 364)

n = 250 271 158

Jacobson IM, et al. AASLD 2010. Abstract 211.



PROVE 3: SVR Rates According to Prior

Response

0

20

40

60

80

100

SV

R (

%)

McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303.

24-wk TVR + P (n = 111)

24-wk TVR + PR + 24-wk PR (n = 113)

12-wk TVR + PR + 12-wk PR (n = 115)

48-wk PR (n = 114)

Prior Nonresponders

39

Prior Relapsers

Prior Breakthrough

38

9 11

69 76

20

42

57

36

62

40

Overall

51*

14

24†

53*

*P < .001 vs control. †P = .02 vs control.


Highlights of AASLD 2012

SVR12 rates similar with TVR BID and q8h dosing regimens in all subgroups

Similar safety and tolerability profile in both treatment arms

OPTIMIZE: Efficacy of Telaprevir BID vs

Telaprevir q8h in GT1 HCV Infection

Buti M, et al. AASLD 2012. Abstract LB-8. Reproduced with permission.

TVR q8h/PR

TVR BID/PR

SV

R1

2 (

%)

0

20

40

60

80

100

CC CT TT

n/ N =

87 92

68 68 65 66

92/ 106

97/ 105

141/ 208

139/ 206

37/ 57

38/ 58

F0-2 F3/4

78 81

59 58

209/ 268

213/ 264

61/ 103

61/ 105

IL28B GT Liver Disease Status

Summary Slide

Much improved SVR rates in treatment naive

and experienced populations

Many are not eligible for these regimens

Side effect profile remains very challenging

Required intensive support and follow-up

Advances Soon to Come

•16

•‡

HCV-specific nucleotide polymerase

inhibitor (chain terminator)

Potent pan-genotypic antiviral

activity against HCV GT1–6

High barrier to resistance

Once-daily, oral, 400-mg tablet

Favorable clinical pharmacology profile

No food effect

No significant drug interactions

Generally safe and well-tolerated in clinical

studies to date (> 2,000 patients)

No safety signal in preclinical/clinical

studies

•Sofosbuvir (SOF, GS-7977)

•17

•‡

• Open label, single arm study of PegIFN-Ribavirin-SOF x 12/52

• Error bars represent 95% confidence intervals

• Lawitz E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #1411

•Phase 3: NEUTRINO GT 1, 4, 5, 6 Treatment-Naïve SVR12 by HCV Genotype

•Pati

en

ts w

ith

HC

V R

NA

<L

LO

Q

(%)

•Overall •GT 1 •GT 4 •GT 5,6

•295/327 •261/292 •27/28 •7/7

•18

•‡

• Error bars represent 95% confidence intervals

• Gane E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #5

•Phase 3: FISSION GT 2, 3 Treatment-Naïve Primary Endpoint and Virologic Response

•Post-treatment

•Week 12

•On treatment

•231/251 •76/241 •249/250 •158/236 •242/244 •207/224

•Week 2 •Week 4 •Week 24 •Pa

tie

nts

wit

h H

CV

RN

A <

LL

OQ

(%

)

•188/190 •NA

•Week 12

•170/253 •162/243

Study met primary endpoint of non-inferiority (P

•SMV 150mg od x 12/52

•91% meet RGT criteria for 24/52

Advanced are soon to come….

Sofosbuvir

Simeprevir

Faldaprevir

Daclatasvir

HIV Experience- still deal with complex patients

and toxicities

Interferon-Sparing Regimens

•Sulkowski. EASL 2013



ELECTRON: Sofosbuvir, GS-5885, and

RBV in Noncirrhotic Pts With GT1 HCV

Interim analysis of nonrandomized phase II study with sofosbuvir (nucleoside polymerase inhibitor) ± GS-5885 (NS5A inhibitor)

SOF + RBV

Wk 12

Treatment naive (n = 25)

SOF + RBV

SOF + GS-5885 + RBV

SOF + GS-5885 + RBV

Null responders (n = 10)

Treatment naive (n = 25)

Null responders (n = 9)

Patients, %

EOT SVR4 SVR12

100 88 84

100 10 10

100 100

100 100*

Gane EJ, et al. AASLD 2012. Abstract 229.

*Data reported for 3 pts only. Data collection ongoing.

No SAEs related to study drugs; AE profile consistent with RBV toxicity profile



AVIATOR: SVR12 Rates With ABT-450/

RTV, ABT-267, ABT-333, and RBV SVR12 rates higher in pts with GT1b HCV but also high in pts with GT1a HCV

– 12-wk regimen with all 3 DAAs + RBV produced highest SVR12 rates

No drug-related SAEs reported; 2 pts discontinued tx due to drug-related AEs

8 wks 12 wks 12 wks

82 86

0

20

40

60

80

100

SV

R1

2 (

%)

96 100 100 100 100 100

84 96

56 24

79

100

29 12

85

100

52 27

83

96

52 25

96 100

54 25

81

100

26 18

89

100

28 17

Observed data

(above bar)

ITT (within bar)

n =

81

98

88 88

100 89

1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450

ABT-267

ABT-333

RBV

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

RBV

ABT-450

ABT-267

ABT-333

RBV

Treatment-Naive Patients Null Responders

Kowdley KV, et al. AASLD 2012. Abstract LB-1. Reproduced with permission.



Response to Daclatasvir, Asunaprevir, and

BMS-791325 in Modified ITT Analysis

Both regimens generally well tolerated, with no discontinuations due to AEs

– Infrequent SAEs, grade 3/4 AEs, or grade 3/4 lab abnormalities

Everson GT, et al. AASLD 2012. Abstract LB-3. Reproduced with permission.

HC

V R

NA

< L

LO

QT

D o

r T

ND (

%)

24-Wk Treatment

(n = 16)

100

80

60

40

20

0 Wk 4 Wk 12 EOT SVR4

100 94 94

94

Missing data HCV RNA < LLOQTD or TND

12-Wk Treatment

(n = 16)

100

80

60

40

20

0

Wk 4 Wk 12 EOT SVR4 SVR12

100 88 100 94 94

HC

V R

NA

< L

LO

QT

D o

r T

ND (

%)

Summary Slide

High SVR rates

Excellent Tolerance

DDI remain an issue

HIV co-infection studies remain to be

conducted

HIV-HCV Co-Infection

Most issues the same

as in HCV mono-

infection

Published trials with

Boceprevir and

Telaprevir

DDI issues

HIV-HCV Guidelines

Sexual Transmission of HCV

Depends on the kind

of sex

Currently an epidemic

in MSM

Treatment of Acute

HCV

Treatment Models

Multi-D maximizes

patient care and

treatment outcomes

How do we get these

clinics funded?

How will this change

over time?

Treat now or Wait?

Treat those who need treatment now

Consider those who are ready for treatment now

You may lose the opportunity later

Treatment will remain difficult to tolerate

Treatment will remain expensive

Who will provide the treatment?.....

Sending the message that HCV treatment is not

important

Funding

Major Issue

Drug costs will

dictate funding

criteria

Who is going to

advocate?

Discussion

CATIE Forum

Reflecting on our response to HCV

1. What is the most effective treatment service delivery model for marginalized HCV clients/patients?

2. What are the challenges for ASOs and other CBOs trying to integrate HCV services into their work?

3. What new linkages could your organization make with other service providers?

Thank you • Next English webinars:

1. Integrated approaches to treatment and prevention July 9, 1pm EST

2. Working from a sexual health or harm-reduction perspective: Integration of HIV, HCV, tuberculosis and other sexually transmitted and blood-borne infections (STBBIs) July 22, 1pm EST

• Please evaluate this webinar!

Documents

New developments in HCV research and their implications ...Highlights From AASLD 2010 SPRINT-2: Response Rates According to Race 0 20 40 40 60 80 80 100 100) SVR Relapse 4-wk PR +