Inibitori delle proteasi di HCV di I generazione: sono una

reale innovazione?

Antonio CraxìGastroenterologia & Epatologia,

Di.Bi.M.I.S.Università di Palermoantonio.craxi@unipa.it

18 Dicembre 2012

• 9 million chronic carriers

• 27,000 to 29,000 newly diagnosed cases per year

• 86,000 deaths per year

• Most affected age group: 25-44 year, followed by 15-24 year

• Clustered to sub-populations

Epidemiology of Hepatitis C in Europe

Van de Laar, Hepatitis Summit Conference, Brussels 2010

Time trends incidence

Map of estimated anti-HCV seroprevalence by GBD region, 2005

Hanafiah et al, Hepatology in press

Treatment of Hepatitis C: Evidence for Effectiveness in SVR Patients

1. Durable HCV-RNA eradication achievable

2. Histological reversal of cirrhosis documented

3. Reduced rates of decompensation and HCC

4. Reduced rates of liver-related mortality

Accessibility to Peg-IFN antiviral therapy in different European countries

Belgium France Germany Italy Spain UK

Pat

ien

ts t

reat

ed p

er 1

00

pre

vale

nt

case

s

HC

V p

reva

len

ce r

ate

(%)

HCV prevalence Treatment levels

0

1

2

3

4

0

2

4

6

8

10

12

14

16

There are substantial differences between European countries in terms of HCV prevalence and access to antiviral therapy

Deuffic-Burban S, et al. Gastroenterology 2012;[ePub ahead of print]Peg-IFN/RBV: peginterferon plus ribavirin

Effect of treatment strategy* according to fibrosis stage on HCV-related cirrhosis and deaths†

*With Peg-IFN + RBV; †All genotypes Deuffic-Burban S, et al. Gastroenterology 2012 [Epub ahead of print]

Cumulative HCV-related cirrhosis and deaths (95% CI)

Treatment scenario Cirrhosis Deaths

With treatment(baseline scenario)

330,700(313,200–342,000)

282,300(268,600–294,200)

Never treating patients with F0/F1

359,300(339,900–372,200)

295,000(280,700–307,700)

Not treating F0/F1 until F2 is reached

332,200(314,600–343,600)

282,700(269,000–294,600)

Not treating F0/F1until F3 is reached

342,400(324,100–354,300)

285,900(272,100–298,000)

• In comparison to the baseline scenario, delaying treatment in patients with F0/F1 is associated with an increase in HCV-related cirrhosis and deaths, regardless of the scenario

• Delaying treatment until F2 is reached appears to be efficient in terms of mortality but will necessitate efficient diagnostic testing of fibrosis to detect progression from F0/F1 to F2

Milestones in Therapy of Genotype 1 HCV

Adapted from US FDA Antiviral Drugs Advisory Committee Meeting; April 27-28, 2011; Silver Spring, MD.

SV

R (

%)

IFN

6 mos

PegIFN/ RBV 12 mos

IFN

12 mos

IFN/RBV

12 mos

PegIFN

12 mos

2001

1998

2011

Standardinterferon

Ribavirin

Peginterferon

1991

Direct-actingantivirals

PegIFN/RBV/DAA

IFN/RBV

6 mos

6

16

3442 39

55

70+

0

20

40

60

80

100

BoceprevirSVR increases from 38% to

63/66% ( + 25-28%)

Naive patients Increased SVR compared to Peg-IFN/RBV

TelaprevirSVR increases from 44% to

72/75%(+ 28-31%)

Poordad F et al. N Engl J Med 2011: 364: 1195-1206Sherman KE et al. Hepatology 2010; 52 (Suppl) : 401A.Jacobson IM et al. Hepatology 2010; 52 (Suppl) : 427A.

BoceprevirRelapsers

SVR increases from 29% to 75%

Partial-Responders SVR increases from 7% to 52%

Treatment-experienced patients Increased SVR compared to Peg-IFN/RBV

TelaprevirRelapsers

SVR increases from 24% to 83/88%

Partial-responders SVR increases from 15% to 54-59%

Null-respondersSVR increases from 5% to 29/33%

Bacon BR., et al. N Engl J Med 2011; 364:1207-1217. Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3Zeuzem S, et al. J Hepatol 2011; 54(Suppl) : S3

Patients Dual Triple Pts # SVR Pts # SVR

Previously untreated 1545 39% 1634

68.5%<2-fold

Relapsers/Partial Resp.

539 26% 719 73% 3-fold

Nonresponders 255 7.5% 386 44% 6-fold

Jurchis AR et al. EASL 2012, Poster 1123 (S442)

Chance for Cure in HCV 1. The Impact of Triple Therapy A Systematic Review

Number of Patients Ever Treated With PEG IFNs per 100 Prevalent HCV Cases until End of 2005

Lettmeier B et al, J Hepatol 2008;49:528-536

Pat

ient

s ev

er tr

eate

d w

ith P

eg-I

FN

s pe

r 10

0 pr

eval

ent c

ases

7000 patients HCV Gt 1 patients treated each year (2008-2011) with a 10% yearly trend to decrease (2010-2011):

– Spontaneous change due to disease epidemiology– Warehousing effect (triple therapy IFN-free)

¼ of Gt 1 patients treated yearly (2008-2010) were re-treatments. This figure has decreased markedly in 2011 (warehousing for triple therapy)

• Yearly expenditure (2011) for P/R: 165,000,000 Euros• Aging population of naives (mean age at tx 48 years) with 25-30% of

F3/F4 fibrosis• At least 20,000 patients with previous P/R failures (usually unclassified)

with a mean age > 55 years and at least 40% of F3/F4 fibrosis

Treatment of HCV genotype 1 in Italy:Treatment of HCV genotype 1 in Italy:the current situationthe current situation

HCV-AIFA Italian study: RVR and SRV to P/R in genotype 1 patients according to baseline factors

MALES

Variables N. of patients RVR SVR

No favorable factors 21/179 (11.7%) 1/19 (5.2%) 3/21 (14.3%)

1 favorable factor 82/179 (45.8%) 17/80 (21.2%) 25/82 (30.5%)

2 favorable factors 62/179 (34.6%) 25/58 (43.1%) 37/62 (59.6%)

3 favorable factors 14/179 (7.8%) 9/14 (64.3%) 12/14 (85.7%)

FEMALES

Variables N. of patients RVR SVR

No favorable factors 58/152 (38.1%) 8/57 (14.1%) 16/58 (27.6%)

1 favorable factor 75/152 (49.4%) 20/70 (28.6%) 26/75 (48.0%)

2 favorable factors 19/152 (12.5%) 12/17 (70.1%) 16/19 (84.2%)

Favorable factors: HCV-RNA < 400,000 UI/mlC/C genotype of rs12979860 SNPNo visceral obesity (VOB)

Favorable factors: Age < 50 years C/C genotype of rs12979860 SNP

First-generation protease inhibitors increase SVR rates in naive and treatment-experienced patients1,2 and may reduce liver-related morbidity and mortality in the long-term1,2

Potential for shorter treatment duration1,2

Not sufficiently tested in difficult patients (cirrhosis)

Modest potency with development of resistance2,3

Genotype 1 restricted

Complex regimens, with risk of poor adherence2

Increased adverse reactions and toxicity burden2

Increased risk of DDIs2

Costs

1. Ghany MG, et al. Hepatology 2011; 54: 1433–442. Ferenci P & Reddy KR. Antivir Ther 2011; 16: 1187–1201

3. Pawlotsky J-M. Hepatology 2011; 53: 1742–51

Advantages Disadvantages

The balance of triple therapy with boceprevir and telaprevir

Addition of BOC or TVR to PegIFN/RBV Improves SVR in Genotype 1 Patients BOC and TVR each indicated in combination with pegIFN/RBV for genotype 1 HCV

patients who are previously untreated or who have failed previous therapy

1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 3. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217. 4. Zeuzem S, et al. N Engl J Med. 2011;364:2417-2428. 5. Bronowicki JP, et al. EASL 2012. Abstract 11.

0

20

40

60

80

100

SV

R (

%)

Relapsers[3,4] Partial Responders[3,4]

PegIFN + RBV

NullResponders[4,5]

BOC/TVR + pegIFN* + RBV

24-29

7-15

29-40

5

69-83

40-59

63-75

38-44

Treatment Naive[1,2]

*BOC was administered with pegIFN-α2b; TVR was administered with pegIFN-α2a in these trials.

Response-Guided Therapy

RGT Paradigm With BOC + PegIFN/RBV in Tx-Naive Patients Indicated for all noncirrhotic treatment-naive patients

BOC + PegIFN/RBV

480 28124

PegIFN/RBV

8 3624

Early response stop at Wk 28; f/u 24 wks

HCV RNA Undetectable Undetectable

480 28124

PegIFN/RBVPegIFN/RBV

8 36

BOC + PegIFN/RBV

24

Slow response extend triple therapy to Wk 36; PR to Wk 48; f/u 24 wks

< 100 IU/mL

< 100 IU/mL

Boceprevir [US package insert]. July 2012. Ghany MG, et al. Hepatology. 2011;54:1433-1444. Boceprevir [EU package insert]. July 2012.

HCV RNA

Detectable Undetectable

Response-Guided Therapy Paradigm With BOC + PegIFN/RBV in Tx-Exp Patients Indicated for noncirrhotic previous relapsers or partial responders*[1,2]

BOC + PegIFN/RBV

480 28124

PegIFN/ RBV

8 3624

HCV RNA Undetectable Undetectable

480 28124

PegIFN/RBVPegIFN/RBV

8 36

BOC + PegIFN/RBV

24

< 100 IU/mL

< 100 IU/mL

1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Boceprevir [EU package insert]. July 2012.

Early response stop at Wk 36; f/u 24 wks

Slow responsePR to Wk 48; f/u 24 wks

*RGT for this group indicated in US only; European prescribing information indicates that noncirrhotic previous relapsers or partial responders should receive 4 wks of pegIFN/RBV followed by 32 wks of BOC + pegIFN/RBV and then 12 wks of pegIFN/RBV, regardless of early response.[3]

HCV RNADetectable Undetectable

RGT With TVR + PegIFN/RBV in Tx-Naive Patients and Previous Relapsers

TVR + PegIFN/RBV

480 24124

eRVR stop at Wk 24, f/u 24 wksPegIFN/RBV

TVR + PegIFN/RBV

480 24124

PegIFN/RBV

HCV RNAUndetectable

Undetectable

Detectable (≤ 1000 IU/mL)

Undetectable or detectable (≤ 1000 IU/mL)

No eRVR extend pegIFN/ RBV to Wk 48; f/u 24 wks

HCV RNA

Indicated for all noncirrhotic treatment-naive pts and previous relapsers*[1,3]

1. Telaprevir [US package insert]. October 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444. 3. Telaprevir [EU package insert]. March 2012.

Undetectable

Undetectable

*AASLD guidelines say RGT “may be considered” for previous partial responders[2] but package inserts recommend 48 wks of therapy.[1,3]

Futility Rules for BOC or TVR + PegIFN/RBV in Tx-Naive and Tx-Exp’d Pts All therapy should be discontinued in patients with the following:

1. Boceprevir [US package insert]. July 2012. 2. Ghany MG, et al. Hepatology. 2011;54:1433-1444.3. Telaprevir [US package insert]. October 2012.

*Assay should have a lower limit of HCV RNA quantification of ≤ 25 IU/mL and a limit of HCV RNA detection of approximately 10-15 IU/mL.

Boceprevir[1,2]

Time Point Criteria* Action

Wk 12 HCV RNA ≥ 100 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue all therapy

Telaprevir[2,3]

Time Point Criteria* Action

Wk 4 or 12 HCV RNA > 1000 IU/mL Discontinue all therapy

Wk 24 HCV RNA detectable Discontinue pegIFN/RBV

Use of HCV RNA Assays in Managing Patients Receiving BOC or TVR A quantitative assay with an LLOQ of ≤ 25 IU/mL and an

LLOD of approximately 10-15 IU/mL must be used

HCV RNA undetectable* (“target not detected”) required to qualify for RGT

– Detectable but < LLOQ is not equivalent to undetectable

– Carefully read HCV RNA assay report to ensure HCV RNA was undetected or “target not detected” before truncating therapy

*An assay with a LLOD of approximately 10-15 IU/mL must be used.

Adverse Events

BOC Plus PegIFN alfa-2b/RBV: Adverse Events Higher rates of anemia, neutropenia, and dysgeusia in

BOC arms vs control

Adverse Event, % PR48 (n = 467)

BOC + PR RGT/48*(n = 1225)

Anemia* 30 50

Neutropenia 19 25

Dysgeusia 16 35*Anemia was managed with RBV reduction and/or epoetin alfa (43% of BOC + PR and 24% of PR).

Boceprevir [US package insert]. July 2012.

TVR Plus PegIFN alfa-2a/RBV: Adverse Events Higher rates of rash, anemia, and anorectal signs and

symptoms in TVR arms vs control

Adverse Event, % PR48 (n = 493)

TVR + PR RGT/48*

(n = 1797)

Rash 34 56

Anemia‡ 17 36

Anorectal events 7 29*Pooled results from TVR arms. †Anemia was managed with RBV dose modification; epoetin alfa was not permitted.

Telaprevir [US package insert]. October 2012.

In most subjects, rash was mild to moderate– Severe rash in 4%; discontinuation due to rash in 6% of

subjects

Cirrhotic Patients

Treatment regimen

Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a + RBV Follow-up

484 160 128Weeks

72

SVR assessment

BOC + Peg-IFN α-2b + RBV Follow-upPeg-IFN + RBV

36

http://www.afssaps.fr/var/afssaps_site/storage/original/application/4b8c53711bab9d8f7d4c3f947caa90f6.pdfhttp://www.afssaps.fr/var/afssaps_site/storage/original/application/fa78af08e029caf9d82bcd9d3e77eb09.pdf

BOC: 800 mg/8h; Peg-IFNα-2b: 1.5 µg/kg/week; RBV: 800 to 1400 mg/day

TVR: 750 mg/8h; Peg-IFNα-2a: 180 µg/week; RBV: 1000 to 1200 mg/day

Interim analysis

Telaprevir: baseline characteristicsTelaprevir

n=292

Male, n (%) 197 (68)

Mean age, range (years) 57.2 (27-83) 54

Mean BMI, SD (kg/m2) 26.5 (4.1)

Genotype 1b / 1a / other (%) 54 / 34 / 12

HCV RNA >800,000 IU/mL, n (%) 181 (62)

Mean Neutrophils, range (109/mm3) 3.3 (0.8-9.7)

Mean Hemoglobin, range (g/dl) 14.6 (9.0-19.7) 15,6

Mean Platelets, range (/mm3) 152,000 (18,000-604,000) 167000

Telaprevirn=292

Mean Prothrombin Time, range (ratio) 86.3 (27-100)

Mean Total Bilirubin, range (µmol/L) 15.4 (4.0-73.5)

Mean Albumin, range (g/dL) 40.1 (20.7-52.0)

Child-Pugh A / B (%) 98 / 2

Mean MELD score, SD 8.1 (2.8)

MELD score <10 / 10 - <13 / ≥13 (%) 81 / 13 / 6

Esophageal varices (%) 33

Realize / Respond-2 exclusion criteria (%) 33 / 46

Telaprevir: baseline characteristics

Patients, n (% patients with at least one event) Telaprevir n=292

Serious adverse events (SAEs)* 132 (45.2%)

Premature discontinuationDue to SAEs

66 (22.6%)43 (14.7%)

DeathSepticemia, Septic shock, Pneumopathy, Endocarditis, Oesophageal varices Bleeding,

5 (2.6%)

Infection (Grade 3/4) 19 (6.5%)

Hepatic decompensation (Grade 3/4) 6 (2.0%)

Asthenia (Grade 3/4) 16 (5.5%)

Rash Grade 3/SCAR 14 (4.8%)

Renal failure 5 (1.7%)

*334 SAEs in 132 patients; SCAR: severe cutaneous adverse reaction

Telaprevir: week 16 safety findings

Patients, n (% patients with at least one event) Telaprevir n=292

Anemia

Grade 2 (8.0 – <9.0 g/dL?)

Grade 3/4 (<8,0 g/dL)

EPO use

Blood transfusion

RBV dose reduction

55 (18.8%)

34 (11.6%)

157 (53.8%)

47 (16.1%)

38 (13.0%)

Neutropenia

Grade 3 (500 – <750/mm3)

Grade 4 (<500/mm3)

G-CSF use

6 (2.0%)

2 (0.7%)

7 (2.4%)

Thrombopenia

Grade 3 (20 000 – <50 000/mm3)

Grade 4 (<20 000/mm3)

Thrombopoïetin Use

28 (9.6%)

9 (3.1%)

4 (1.4%)

EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor

Telaprevir: week 16 safety findings

Boceprevir: baseline characteristicsBoceprevir

n=205

Male, n (%) 140 (68)

Mean age, range (years) 56.9 (34-81)

Mean BMI, SD (kg/m2) 26.2 (4.1)

Genotype 1b / 1a / other (%) 50 / 40 / 10

HCV RNA >800,000 IU/mL, n (%) 131 (64)

Mean Neutrophils, range (109/mm3) 3.3 (0.5-8.5)

Mean Hemoglobin, range (g/dl) 14.8 (9.7-18.4)

Mean Platelets, range (/mm3) 146,000 (33,900-346,000)

Boceprevirn=205

Mean Prothrombin Time, range (ratio) 87.3 (23-100)

Mean Total Bilirubin, range (µmol/L) 15.0 (4.0-78.0)

Mean Albumin, range (g/dL) 40.4 (27.0-50.3)

Child-Pugh A / B (%) 99 / 1

Mean MELD score, SD 8.1 (3.0)

MELD score <10 / 10 - <13 / ≥13 (%) 83 / 12 / 5

Esophageal varices (%) 40

Realize / Respond-2 exclusion criteria (%) 29 / 40

Boceprevir: baseline characteristics

Patients, n (% patients with at least one event) Boceprevir n=205

Serious adverse events (SAEs)* 67 (32.7%)

Premature discontinuationDue to SAEs

54 (26.3%)15 (7.3%)

DeathPneumopathy

1 (0.5%)

Infection (Grade 3/4) 5 (2.4%)

Hepatic decompensation (Grade 3/4) 6 (2.9%)

Asthenia (Grade 3/4) 12 (5.8%)

Rash Grade 3/SCAR 0

Renal failure 0

*159 SAEs in 67 patients; SCAR: severe cutaneous adverse reaction

Boceprevir: week 16 safety findings

Patients, n (% patients with at least one event) Boceprevir n=205

Anemia

Grade 2 (8.0 – <9.0 g/dL)

Grade 3/4 (<8,0 g/dL)

EPO use

Blood transfusion

RBV dose reduction

48 (23.4%)

9 (4.4%)

95 (46.3%)

13 (6.3%)

22 (10.7%)

Neutropenia

Grade 3 (500 – <750/mm3)

Grade 4 (<500/mm3)

G-CSF use

2 (1.0%)

7 (3.4%)

9 (4.4%)

Thrombopenia

Grade 3 (20 000 – <50 000/mm3)

Grade 4 (<20 000/mm3)

Thrombopoïetin Use

10 (4.9%)

3 (1.5%)

2 (1.0%)EPO: Erythropoïetin; G-CSF: granulocyte-colony stimulating factor

Boceprevir: week 16 safety findings

Multivariate analysis: baseline predictors of severe complications*

* Death, severe infection and hepatic decompensation, n=32

Predictors OR 95%CI p-value

Prothrombin Time

(per unit decrease)

1.03 1.01-1.06 0.038

Age(per year increase)

1.05 1.01-1.11 0.025

Platelet count≤100,000/ mm3

3.19 1.32-7.73 0.0098

Albumin level<35 g/L

4.95 2.04-12.01 0.0004

Multivariate analysis: predictors of anemia <8g/dL or blood transfusion *

Predictors OR 95%CI p-value

Age(per year increase)

1.06 1.026-1.09 0.0003

Gender(Female)

2.32 1.10-4.35 0.023

No lead-in phase 2.33 1.22-4.35 0.01

Hemoglobin level≤12 g/dL for female ≤13 g/dL for male

5.85 2.83-12.08 <0.0001

* n=71

Telaprevir: week 16 efficacy dataPer protocol

0

10

20

30

40

50

60

70

80

90

100

Week 4 Week 8 Week 12 Week 16

ITT

58%55%

92%

80%

93%

79%

92%

67%

Pat

ien

ts w

ith

un

det

ecta

ble

HC

V R

NA

(%

)

161/276 161/292 236/257 236/292 230/247 230/292 196/212 196/292

Telaprevir: Week 16 efficacy according to prior treatment response (ITT)

NullResponse

Partial Response

Relapse0

10

20

30

40

50

60

70

80

Pat

ien

ts w

ith

un

det

ecta

ble

HC

V R

NA

(%

)

46%

66%

75%

11/24 90/136 92/123

P=0.005

Boceprevir: week 16 efficacy data

0

10

20

30

40

50

60

70

80

90Per protocol

ITT

Pat

ien

ts w

ith

un

det

ecta

ble

HC

V R

NA

(%

)

Week 4 Week 8 Week 12 Week 16

3% 2%

42%38%

64%

55%

77%

58%

5/194 5/205 77/181 77/205 112/174 112/205 118/154 118/205

Boceprevir: Week 16 efficacy according to prior treatment response (ITT)

0

10

20

30

40

50

60

70

80

NullResponse

Partial Response

Relapse

22%

50%

69%P=0.001

2/9 45/90 69/100

Rationale for Prompt Treatment of HCV

HCV is a progressive disease, associated with persistence of viral replication and ongoing necroinflammation and fibrosis

Remission (SVR) is associated with loss of active viral replication and improvement in hepatic fibrosis

Important questions

– Does that equate to a need to treat all patients?

– Can we avoid losing time for patients destined to progress?

– How do we avoid unnecessary or detrimental treatment when there are improved treatments pending?

Indications for Treatment of Chronic HCV Infection All patients, regardless of the degree of fibrosis, are

potential candidates for treatment

IFN-based therapy is current standard of care

Patients with mild disease may not require immediate treatment

For those who require treatment

– Patients should be fit for the regimen

– Patients should have the ability to adhere to treatment goals and monitoring

There is a complex ongoing debate regarding opportune timing for treatment given the therapeutic landscape

Pts Who Want TxWant to be cured of disease

Personal or social reasons

Plans for pregnancy

Social support

Eligible for reimbursement now

Pts Who Are Eligible for Tx

Eligible for pegIFN/ RBV

Fit for regimen

No contraindications

Disease stage

Pts Who Are Motivated and Understand . . .

Likelihood of response

Risks/benefits of treatment

Risk of resistance

Possibility of shortened therapy

What is “coming down the line” for their genotype

Who Should Be Treated Now?

Severity of Disease Increases Need for HCV Therapy but Also Impairs Response

May not need immediate treatment

BUT Easier to treat High likelihood of

response

Advanced disease/ cirrhosis

Mild disease

Greater need for treatment BUT

Response may be impaired Perhaps more effective options in

future, but efficacy of some investigational agents may be unclear due to trial eligibility criteria

What Are the Chances of Being Cured With Current Therapy?

Black Cirrhosis Genotype 1

(1a worse than 1b) IFN nonresponsive IL28B TT

Favorable prognostic factors

Less favorable prognostic factors

White No fibrosis Genotype 2/3 IFN responsive (eg,

RVR/EVR or response to lead-in)

Previous relapser IL28B CC

Limitations of Current Regimens and Prospects for Future Regimens

Current

Must be eligible for pegIFN/ RBV

Large pill burden, TID dosing of PIs (at present); parenteral IFN

Challenging adverse events

High likelihood of resistance with treatment failure

Current PIs only effective for genotype 1

Possibility of resistance with poor adherence

Future

Perhaps IFN free

Lower pill burden, less than TID dosing; perhaps all oral

May be better tolerated

May not generate resistance

Pangenotypic or at least more

Higher barrier to resistance with some classes

Challenging Patients for Whom Treatment With Current Options Less Than Optimal

Cirrhosis (all genotypes)

Decompensated cirrhosis

Null responders

Pretransplantation

Posttransplantation

Renal failure

– Impaired renal function

– Dialysis

– Renal transplantation recipients

Injection-drug users

– Methadone substitution

Thalassemics

Children

IFN contraindicated

IFN intolerant

Those on “edge” of society

Psychiatric comorbidity

No SVR

SVR100

Pat

ien

ts W

ith

Liv

er

Co

mp

licat

ion

s (%

) 80

60

40

20

01680 24 48 72 96 120 144

Mos

759 124

702119

634116

527108

34570

20741

3412

Cumulative Incidence of Liver-Related Complications Following SVR in Cirrhosis

Bruno S, et al. Hepatology. 2007;45:579-587.

Pts at Risk, n

SVR to Telaprevir in Treatment-Naive Pts With GT1 HCV and Compensated Cirrhosis

Kauffman RS, et al. HepDart 2011. Abstract 52.

79

46

92 90

66

7471

38

61

92

50 51

0

20

40

60

80

100

T12PR PR48 T12PR24 T12PR48 T12PR48 T12PR

AllCirrhosis

ADVANCE ILLUMINATE

eRVR+* eRVR-* Overall

n/N= 285/363

15/21

166/361

SV

R (

%)

8/21

149/162

144/160

78/118

398/540

11/18

11/12

6/12

31/61

*eRVR+ randomized: 60% (322/540); eRVR-: 22% (118/540).

CUPIC: Efficacy of TVR in Cirrhotics

~ 80% of patients treated with TVR-based therapy had undetectable HCV RNA at end of 16 wks of triple therapy

Hezode C, et al. AASLD 2012. Abstract 51.

0

20

40

80

100

Un

det

ecta

ble

HC

V R

NA

(%

)

60

145/276

53

Wk 4 Wk 8 Wk 12 Wk 16

145/285

224/265

224/282

219/254

219/281

177/205

177/251

51

8579

8678

86

71

Per protocolITT

n/N =

CUPIC: Efficacy of Boceprevir in Cirrhotics ~ 60% of patients treated with BOC-based therapy had

undetectable HCV RNA at Wk 16 of ongoing therapy

2/155

1

Wk 4 Wk 8 Wk 12 Wk 16

2/155

55/149

55/150

88/144

88/151

89/126

89/146

1

37 37

61 58

71

61

Un

det

ecta

ble

HC

V R

NA

(%

)

n/N =

Per protocolITT

0

20

40

80

100

60

Hezode C, et al. AASLD 2012. Abstract 51.

The First-Generation Protease Inhibitors: Where Are We Now? Telaprevir and boceprevir are harbingers of important treatment

advance

Improved SVR rates in both naive and experienced patients

Certain patients (advanced disease) require therapy imminently and should be treated now

Others may be motivated to be treated now—opportunities for cure, candidates for shortened therapy, and/or personal reasons

For many, the choice is not clear

The advent of triple therapy changes the way treatment discussed with patients

– Clinicians must educate and advocate for patients to choose the correct course of treatment

Factors That Influence Outcomes With HCV Therapy

SPRINT-2: Influence of Baseline Patient and Virus Factors on SVR With BOC

BOC + pegIFN-α2b/RBV RGTBOC + pegIFN-α2b/RBV 48 wks

1. Poordad F, et al. N Engl J Med. 2011;364:1195-1206. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

93/133

89/134

100

0

50

1b 1aGenotype[1]

70 66

≤ 800,000 > 800,000 HCV RNA (IU/mL)[1]

85

76

F0-2 F3/F4Fibrosis[1]

6767

SV

R (

%)

75

25

41/54

45/53

213/319

211/313

n/N =n/N =

63 5963 61

41

52

118/187

106/179

14/34

22/42

192/314

197/313

44/55

82/115

26/44

CC CT TT

80

71

59

IL28B[2]

1b 1aGenotype[1]

< 800,000 ≥ 800,000HCV RNA (IU/mL)[1]

F0-2 F3/F4Fibrosis[1]

ADVANCE: Influence of Baseline Patient and Virus Factors on SVR With TVR Data from TVR12 + pegIFN-α2a/RBV arm only

1. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

CC CT TT

IL28B*[2]

152/213

118/149

100

0

50

7971

7874

62

78

SV

R (

%)

75

25

207/281

64/82

45/73

226/290

n/N =n/N =

45/50

48/68

16/22

90

71 73

*IL28B testing was in whites only.

IL28B Genotype Predicts Likelihood of Eligibility for Shortened Therapy

1. Poordad F, et al. Gastroenterology. 2012;143:608-618. 2. Jacobson IM, et al. EASL 2011. Abstract 1369.

SPRINT-2: BOC + PegIFN-α2b/RBV [1]

Eli

gib

ilit

y fo

r R

GT

(%

)

117/132

158/304

CC CT/TT

89100

80

60

40

20

0

52

ADVANCE: T12 + PegIFN-α2a/RBV *[2]

Eli

gib

ilit

y fo

r R

GT

(%

)

39/50

39/68

10/22

78

100

80

60

40

20

0

57

45

n/N =

*IL28B testing in ADVANCE was in whites only.

CC CT TT

n/N =

IL28B Genotype Should Not Be Used to Exclude Patients From Therapy If patients have favorable CC genotype

– Likelihood of SVR is high with pegIFN/RBV alone, but triple therapy may allow shorter therapy and, in one TVR study, higher SVR rates[1]

If patients have unfavorable CT/TT genotype

– Likelihood of SVR is higher with triple therapy than with pegIFN/RBV

– 59% to 71% in SPRINT-2[2]

– 71% to 73% in ADVANCE*[1]

Limited value of IL28B genotyping in treatment-experienced patients

– Most have unfavorable TT or CT genotype

1. Jacobson IM, et al. EASL 2011. Abstract 1369. 2. Poordad F, et al. Gastroenterology. 2012;143:608-618.

*IL28B testing in ADVANCE was in white Americans only.

Lead-in Strategies

Lead-in Strategy Can Help Determine Whom to Treat 4 wks of pegIFN/RBV lead-in before BOC (or TVR)

– Lowers HCV RNA burden

– May identify rapid responders who may not need DAA

– Allows assessment of IFN responsiveness

– Provides useful information regarding likelihood of SVR with addition of DAA

– Provides insight into tolerability of pegIFN/RBV backbone

– Elucidates hematologic response to pegIFN/RBV, especially in “marginal” patients; make needed dose adjustments before addition of DAA

Early IFN Response (Lead-in) Further Defines Likelihood of SVR for Non-CC Pts A > 1 log10 decrease in HCV RNA at Wk 4 of therapy is the strongest

predictor of SVR

0/2

2/3

2/4

56/75

83/102

58/72

1/27 19/

5120/45

37/117

83/111

109/133

1/20 6/

2510/25

13/26

23/28

26/34

CC CT TT

≥ 1 log ≥ 1 log ≥ 1 log

SV

R (

%)

SPRINT-2 and RESPOND-2 Combined100

80

60

40

20

0

67

50

7581 81

4

3744

32

7582

5

24

40

50

8276

PegIFN-α2b/RBV*

BOC + pegIFN-α2b/RBV RGT*

BOC + pegIFN-α2b/RBV 48 wks*

< 1 log < 1 log < 1 log

n/N=

Poordad F, et al. Gastroenterology. 2012;143:608-618.*BOC was administered with pegIFN-α2b in these trials.

Preparing for Treatment:Possibilities of

Drug–Drug Interactions

TVR

– Substrate of CYP3A

– Inhibitor of CYP3A

– Substrate and inhibitor of P-gp

Both BOC and TVR Have Potential for Many Drug–Drug Interactions BOC

– Strong inhibitor of CYP3A4/5

– Partly metabolized by CYP3A4/5

– Potential inhibitor of and substrate for P-gp

Most drug–drug interactions can be overcome by careful survey of the patient’s medications and judicious substitutions during HCV therapy (or just during the period of PI-based triple therapy)

Medicines That Are Contraindicated With BOC and TVR

1. Boceprevir [package insert]. July 2012. 2. Telaprevir [package insert]. October 2012.

Drug Class* Contraindicated With BOC[1] Contraindicated With TVR[2]

Alpha 1-adrenoreceptor antagonist

Alfuzosin Alfuzosin

Anticonvulsants Carbamazepine, phenobarbital, phenytoin

N/A

Antimycobacterials Rifampin Rifampin

Antiretrovirals EFV, all RTV-boosted PIs DRV/RTV, FPV/RTV, LPV/RTV

Ergot derivatives Dihydroergotamine, ergonovine, ergotamine, methylergonovine

Dihydroergotamine, ergonovine, ergotamine, methylergonovine

GI motility agents Cisapride Cisapride

Herbal products Hypericum perforatum (St John’s wort) Hypericum perforatum

HMG CoA reductase inhibitors

Lovastatin, simvastatin Lovastatin, simvastatin

Oral contraceptives Drospirenone N/A

Neuroleptic Pimozide Pimozide

PDE5 inhibitor Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN

Sildenafil or tadalafil when used for treatment of pulmonary arterial HTN

Sedatives/hypnotics Triazolam; orally administered midazolam

Orally administered midazolam, triazolam

*Studies of drug–drug interactions incomplete.

Preparing for Treatment:Management of Adverse Events

Adverse Effect Management: Anemia

Recommendation: anemia should be managed initially by reducing the RBV dose[1]

Do not dose reduce DAA or stop and then restart

Do not discontinue pegIFN/RBV and continue DAA

Monitor closely if Hb falls < 10 g/dL

ESA agents are unlabeled for HCV anemia

– May be effective as a secondary anemia management strategy

1. Ghany MG, et al. Hepatology. 2011;54:1433-1444.

EPO and RBV Dose Reduction for Anemia Lead to Similar SVR Rates in BOC Patients Nested study within randomized trial of genotype 1 HCV therapy-naive patients

receiving 4 wks of lead-in with pegIFN-α2b/RBV and then either 44 wks of triple therapy or RGT (24-44 wks)

Poordad F, et al. EASL 2012. Abstract 1419.

0

20

40

80

100S

VR

(%

)

RBV DR EPO

∆ -0.7% (95% CI: -8.6 to 7.2)*

71 71

178/249 178/251n/N =

*Stratum-adjusted difference in SVR rates, adjusted for stratification factors and protocol cohort.

60

82% of RBV dose reduction group vs 62% in EPO group did not require secondary anemia intervention

Predictive Value of Anemia for SVR With BOC or TVR

1. Sulkowski MS, et al. Hepatology. 2012;[Epub ahead of print]. 2. Poordad F, et al. DDW 2011. Abstract 626.

5858

7272 7373 7474

SV

R (

%)

SV

R (

%)

SPRINT-2*[1]SPRINT-2*[1]

Hb ≥ 10 g/dLHb ≥ 10 g/dLHb < 10 g/dLHb < 10 g/dL

n/N =n/N =0

20

40

60

80

100

212/363 263/363 n/N =n/N =0

20

40

60

80

100

267/361384/524

ADVANCE and ILLUMINATE†[2]ADVANCE and ILLUMINATE†[2]

†Data from T12/PR arm only.†Data from T12/PR arm only.*Data from BOC/48 and BOC RGT arms.*Data from BOC/48 and BOC RGT arms.

In phase III trials, anemia positive predictor of SVR with BOC[1] but not TVR[2]

EOTR, relapse, and SVR comparable between RBV DR and EPO arms in treatment-naive patients who developed anemia during BOC/PR therapy[1]

Adverse Effect Management: Rash and Anorectal Symptoms Rash management

– Mild to moderate rash can be treated with oral antihistamines, topical steroids

– Systemic steroids are not recommended

– For severe rash, many practitioners will stop TVR alone and follow for 1 wk to see if the rash improves

– If not, stop all 3 drugs

– Important to have “go-to” dermatologist; vigilance with rash is key

Anorectal symptom management

– Fiber, loperamide, hydrocortisone, pramoxine topical cream, topical lidocaine

Managing Major Adverse Effects of PegIFN

Depression

– Assess mood, sleep, suicidal thoughts

– Consider SSRI to treat baseline or new depression

– Refer to mental health services to follow high-risk patients during treatment

Influenzalike symptoms

– Acetaminophen, hydration

– Reduce dose of IFN if necessary

Neutropenia, thrombocytopenia: monitor CBC frequently

Others: GI upset, hair loss, insomnia, injection-site reactions

Helping Patients Adhere to Complex Regimens PegIFN/RBV + BOC or TVR = very complex regimen

– BOC 800 mg TID: 12 pills/day with food

– TVR 750 mg TID: 6 pills/day with high-fat meal

– RBV (2-6 pills/day) and weekly pegIFN injection

Adherence enhanced by a combination of

– Patient education and motivation

– Reducing pill burden when possible

– Shortening therapy when appropriate

– Prompt adverse effect management

Optimizing Current HCV Therapy With PIs Plus PegIFN/RBV

Strategies to Enhance Current Therapy With PegIFN/RBV Plus PI for GT1 Pts Shorter therapy may be possible for certain patients

– Investigational T12/PR12 regimens for IL28B CC patients

PR alone for IL28B CC patients?

– Being evaluated in phase III trial vs BOC + pegIFN-α2a/RBV

Potential for BID dosing of TVR

– OPTIMIZE[1]: TVR 1125 mg BID noninferior to TVR 750 mg every 8 hrs (both with pegIFN-α2a/RBV) in treatment-naive GT1 patients

– SVR12 in 74% vs 72% of patients, respectively

– No increase in adverse events

1. Buti M, et al. AASLD 2012. Abstract LB-8.

NAIVES: RESULTS (SVR)

• BOC-RGT

• TVR-RGT

Universal treatment

• BOC-RVR

• TVR-IL28

Selective treatment

SVR % ICER ( )€

74.5

67.0

72.1

79.0

118,000

85,000

56,000

74,000

NAIVES: RESULTS (LYG)

• BOC-RGT

• TVR-RGT

Universal treatment

• BOC-RVR

• TVR-IL28

Selective treatment

LYG (yrs) ICER ( )€

4.18

3.75

4.04

4.42

19,200

13,400

8,300

11,400

ICER/LYG different clinical settings

ICER = < 12.000 € triple therapy for naives

ICER = 60.000 € erlotinib pancreatic cancer

ICER = 15.000 € Heart transplantation

ICER = 74.000 € sorafenib HCC

Naives: key points

Triple therapy with first-generation PIs in naïve Gt 1 CHC patients:

• is optimised by allocating patients according to IL28B and/or RVR based strategies

• improves survival by about 4 years

• is cost-effective, with an ICER per LYG below € 12,000

• is strongly influenced by the IL28B CC prevalence and the ensuing likelihood of RVR and SVR, but also by the pricing of BOC and TVR

- An individualized treatment strategy can avoid triple therapy in 25-33% of naive HCV G1 patients

FULL PAPERS

ABSTRACTS

Re-treatment with P/R of treatment-experienced patients

Overall SVR rate after retreatment: 16.1% (CI 6-33%)

Cammà C, et al. J Hepatol. 2009 Oct;51(4):675-81.

EASL and AASLD Guidelines recommend that G1 HCV patients failing to eradicate HCV on P/R should not be retreated with P/R alone

Phase 3 RCTs (BOC: RESPOND-2, PROVIDE: TVR: REALIZE) show that TT achieves SVR in about 30%-75% of experienced G1 CHC patients, with SVR rates progressively decreasing from :

• Relapse (RR) • Partial responders (PAR) (HCV-RNA drop >2 log at week 12, but never not detectable)• Null responders (NR) (HCV-RNA drop < 2 log at week 12).

Re-treatment with P/R plus a 1st generation PI

of treatment-experienced patients

Competing strategies

• BOC LEAD IN

• TVR LEAD IN

• BOC-POOR§

• BOC-GOOD*

• TVR-POOR §

Response to previous P/R

• TVR NO LEAD IN

• TVR-GOOD*

Strategy

*>1Log drop at week 4 of DT§<1Log drop at week 4 of DT

Responseto lead-in

• RR

• PAR

• NR

Cammà C, et al. J Hepatol, in press

Cost-effectiveness of Boceprevir or Telaprevir for previously treated

patients with Gt 1 CHC

0

2000

4000

6000

8000

10000

12000

14000

16000

18000

20000

F3-F4RR

F3-F4PAR

F3-F4NR

CHCRR

CHCGOOD

CHCPAR

CHCPOOR

CHCNR

ICER

for L

YGICERs According to Profile of Previous

Response and Severity of Liver Fibrosis

TVR

BOC

Cammà C, et al. J Hepatol, in press

CAVEATS

• Efficacy data from registration trials

• Inconclusive data on cirrhosis

• Aggregate rather than individual patient data

• Analysis limited to direct medical costs

• Time horizon = 20 years

• Local disease epidemiology and cost issues do not allow universal use of triple therapy (TT) in Italy

• Patients with F3/F4 fibrosis deserve priority for TT• Selected patients with F0/F2 fibrosis may benefit from TT• Some non-responders should not be retreated with currently

available therapies• Boceprevir and telaprevir are equally effective• Only Centers who meet specific requirements are allowed to

prescribe TT• HCV monoinfected and HCV/HIV coinfected patients should both

receive access to TT• TT after OLT can only be used off-label (law 648/96)

Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:basic principles (presumably) followed by AIFAbasic principles (presumably) followed by AIFA

• IL28b status and virological features (baseline viral load and HCV subtype) are weak predictors at the individual level of RVR and SVR and cannot be used to pre-assign to TT or P/R

• Response to a lead-in phase (P/R alone for 4 weeks>1 log drop in HCV RNA from baseline) is the strongest predictor of SVR*, and its absence of appearance of RAVs, hence a lead-in period is enforced for both boceprevir and telaprevir to:– Rule-in naïve patients in need of TT– Rule-out treatment experienced patients with a low likelihood of

response to TT

Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:basic principles (presumably) followed by AIFAbasic principles (presumably) followed by AIFA

* Proven for boceprevir, assumed for telaprevir

Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:AIFA criteria for naive Gt 1 patientsAIFA criteria for naive Gt 1 patients

Fibrosis stage

Triple therapy (P/R with Boc or Tpv)

Dual therapy (P/R)

Comments

F0, F1, F2 RVR* negative RVR* positive

F3, F4 All patients None

Lead-in not needed for telaprevir

* RVR: at least 1 log10 drop after 4 weeks of P/R

Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy: AIFA criteria for treatment exp. Gt 1 patients AIFA criteria for treatment exp. Gt 1 patients

Fibrosis stage Triple therapy (P/R with Boc or Tpv)

Dual therapy

(P/R)

Comments

F0, F1, F2

RR: allPR: all

NR: only if RVR* positiveUK: only if RVR* positive

None

F3, F4 All patients NoneLead-in not needed for telaprevir

* RVR: at least 1 log10 drop after 4 weeks of P/R

RR: relapsers; PR: partial responders; NR: null responders; UK: unknown pattern

• AIFA criteria are partly hypothetical:• Lead-in largely unproven for telaprevir• No statements about indications for treatment (Do all patients with

F0/F2 fibrosis deserve therapy? What policy for informed deferral)?• Assimilating an unknown response to null response may be

unsound• Unclear diagnostic criteria for fibrosis• Efficacy in terms of cost reduction may be insufficient

• 20% of naïve patients• 30-40% of treament experienced patients

• Selection of Centers for treatment is delegated to regional Health Authorities, who are also empowered to impose further restrictions

Approval of triple therapy for reimbursement in Italy:Approval of triple therapy for reimbursement in Italy:potential critical issuepotential critical issue

The Future of HCV Therapy

Investigational Agents for HCV

Interferons Antiviral agents

Therapeuticvaccines

Hosttarget

Replication, polyprotein processing and/or assembly

Entry

NS5Bpolymerase inhibitors

NS3protease inhibitors

NS5Areplication complex inhibitors

miRNA-122 Cyclophilin

Cyp

inhibitors

Drugs in the HCV pipeline (November 2012)

Approved

Boceprevir

Telaprevir

Protease Inh (PI)Polym Inh (nuc)Polym Inh (nn)NS5A (RCI) InhOther (misc mechs)

Former IDs:1 ACH-1625 2. RG7227 (ITMN-191) 3 SH9005182 4 RG-7128; RO5024048 5 GS-9190 6 RG77907 BMS-0032 8 MK-7009 9 BMS 790052 10 Deb02511 BI-201335

BI-207127

RBV

Peg-IFNα-2B

Peg-IFNα-2a

Phase 2

Danoprevir2

GS 9256

GS 9451

Narlaprevir3

Mericitabine4

INX-189

VX-222

BI 207127

IDX-375

miR-122 a-s*

BMS 791325

Sovaprevir1

ABT 072

GS-9254

GS-9669

GSK 2336805

IDX 719

GS-5885

ABT-267

Silymarin (IV)

CT-011 mAb*

GS6624 mAb*

Celgosivir

GS-9620 TLR7

GI-2005

Ad3NSmut*

Setrobuvir6

Tegobuvir5

BMS 824393 *

Phase 3

Simeprevir

Alisporivir10

ABT-333

Daclatasvir9

Peg-IFNλ-3

Asunaprevir7

ABT-450/r

Vaniprevir8

Faldaprevir11

IDX-184X

X

Sofosbuvir

*

*

*

*ALS 2200

Characteristics of HCV DAA classesCharacteristic Protease

inhibitorsNucleos(t)ide polymerase inhibitors

Non-nucleoside polymerase inhibitors

NS5a inhibitors

Potency High, variable among HCV

geno/subtypes

Moderate-high, consistent across geno/subtypes

Variable, variable across

geno/subtypes

High, multiple HCV genotypes

Barrier to resistance

Low1a < 1b

High1a = 1b

Very low1a < 1b

Low1a < 1b

DDI potential High Low Variable Low-moderate

Toxicity RashAnemia

Bilirubin

Mitochondrial nucleos(t)ide

interactions (ART, RBV)

Variable Variable

Pharmacokinetics Variable: QD to TID

QD Variable: QD to TID

QD

Comments 2nd generation Pis: better barrier, pangenotypic

Single target active site

Allosteric inhibition, many

targets

Multiple mode of action

Kieffer T, et al. J Antimicrob Chemother 2010;65:202–12Gao M, et al. Nature 2010;465:96–100; Lagrace L, et al. Hepatology 2010;52(4 Suppl):1205A

Lenz O, et al. Hepatology 2010;52(4 Suppl):709A; Zeuzem S, et al. Hepatology 2010;52(4 Suppl):400A

R: resistant (>4-fold increase in EC50)S: susceptible (<4-fold change in EC50)

No cross resistance between classes: a combination of DAAs can eliminate RAVs

HCV therapy: hopes and hypes….• Interferon-free• >90% SVR• Once daily• High tolerability with low adverse event• Few drug-drug interactions• Short, fixed duration (12-24 weeks)• Pan-genotypic• High barrier to resistance or lack of cross

resistance• Affordable

IL28B genotype has been associated with viral kinetics during IFN-free therapy

INFORM-1 : Mericitabine (NI) + danoprevir (PI), 14 days, n = 15

Chu, Gastro , 2012

•Regimens With 1 DAA + PegIFN alfa/RBV

•Regimens With 2 DAAs

+ PegIFN alfa/RBV•IFN-Free Regimens

Faldaprevir* (BI 201335, PI)

Daclatasvir* (BMS-790052, NS5A)

Sofosbuvir* (GS-7977, NI)

Simeprevir* (TMC435, PI)

Alisporivir* (CYP) On Hold

Vaniprevir (MK-7009, PI)

Daclatasvir + asunaprevir* Sofosbuvir + RBV

Sofosbuvir + GS-5885 (FDC) ± RBV

Daclatasvir + asunaprevir

ABT-450/RTV + ABT-267 ± ABT-333 ± RBV

Investigational HCV Regimensin Phase III Clinical Trials

•New Interferons

PegIFN lambda-1a + RBV

PegIFN lambda-1a + daclatasvir + RBV

ClinicalTrials.gov.

•Alternative Dosing

TVR BID* (approved PI)

*Studied with pegIFN-α2a. Studied with both pegIFN-α2a and pegIFN-α2b.

Interferon Plus DAA-Based Regimens

ASPIRE: Simeprevir (TMC435) 150 mg for 12, 24, 48 Wks + PR in Tx-Exp’d GT1 Pts SVR24 rates according to previous response category[1]

High rates of efficacy in patients with METAVIR F3/F4 fibrosis [2]

` Relapsers: 65%; partial responders: 67%; null responders: 33%

Simeprevir 150 mg* + pegIFN-α2a/RBV 48 wks

Placebo + pegIFN-α2a/RBV 48 wks

*Pooled.

80

SV

R24

(%

)

0

40

60

100

20

Relapsers Partial Responders

Null Responders

37

85

9

76

19

51

1. Jacobson I, et al. IDSA 2012. Abstract 1287. 2. Poordad F, et al. AASLD 2012. Abstract 83.

10/27

67/79 2/23

52/69

26/51

3/16

n/N =

ATOMIC: Sofosbuvir (GS-7977) Plus PR in Treatment-Naive GT1 Patients Interim analysis of randomized, open-label phase II study

Kowdley KV, et al. EASL 2012. Abstract 1. Hassanein T, et al. AASLD 2012. Abstract 230.

Treatment-naive,

noncirrhotic patients*(N = 332)

Sofosbuvir + PegIFN-α2a/RBV

(n = 52)

Sofosbuvir + PegIFN-α2a/RBV(n = 125)

Sofosbuvir + PegIFN-α2a/RBV

(n = 155)

Wk 24Wk 12

Sofosbuvir (n = 75)

Sofosbuvir + RBV(n = 75)

*All infected with genotype 1 HCV, except for 16 patients with GT4 or 6 HCV who were eligible for 24-wk arm of sofosbuvir plus PR.

SVR12,%

90

92 overall

82 GT4

100 GT6

91

Interferon-Free Regimens

ELECTRON: Sofosbuvir and RBV in Naive and Experienced GT1 Patients

Wk 12Wk 12

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

Sofosbuvir + RBV 1000/1200 mg (GT1; naive) (n = 25)

Sofosbuvir + RBV 1000/1200 mg (GT1; null responders) (n = 10)

SVR12

10

Wk 8Wk 8

84

Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; naive) (n = 25)

SVR4

100

Viral Response, %

Sofosbuvir + GS-5885 + RBV 1000/1200 mg (GT1; nulls) (n = 9) 100*

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

NIH SPARE: Interim Data on Sofosbuvir and RBV in Difficult-to-Treat GT1 Patients Patients with poor prognostic indicators: GT1a (70%), male (63%), black (83%), IL28B CT/TT (80%), advanced liver disease (22%)

Median BMI: 28; median HCV RNA: 6.4 logs

Wk 24Wk 24 SVR4

Osinusi A, et al. AASLD 2012. Abstract LB-4.

Sofosbuvir + RBV 1000/1200 mg (n = 10)

Sofosbuvir + RBV 1000/1200 mg (n = 25)

Sofosbuvir + RBV 600 mg (n = 25)

Part 1 (early-stage fibrosis) SVR12

90*

Part 2 (all stages of fibrosis)

56†

72*

EOT

90*

88†

96*

Viral Response, %

*1 dropout at Wk 3. †3 dropouts by Wk 8.

90*

Daclatasvir Plus Sofosbuvir ± RBV in Treatment-Naive GT1 or 2/3 Patients No impact of RBV on viral response

Treatment-naive, noncirrhotic

patients

GT1a or 1b (n = 44)

GT2 or 3 (n = 44)

Daclatasvir + SofosbuvirSofosbuvir

Daclatasvir + Sofosbuvir

Daclatasvir + Sofosbuvir + RBV

Wk 1 Wk 24

Sobosbuvir dosed 400 mg QD. Daclatasvir dosed 60 mg QD. RBV dosed by body weight for GT1 patients (1000-1200 mg/day); 800 mg/day for GT2/3 patients.

Sulkowski MS, et al. AASLD 2012. Abstract LB-2.

GT1

93

100

100

GT2/3

88

100

93

SVR24, %

AVIATOR: IFN-Free Regimens With ABT-450/RTV, ABT-267, ABT-333, and RBV

Cohort 1:Treatment-naive pts, GT1 HCV

ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV

(n = 80)

ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV

ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV

ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV

ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV

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

Phase II trial with 2 cohorts SVR12, %

87.5

97.5

Wks 0 8 12 24

NR

Cohort 2:Tx-exp’d pts, GT1 HCV, with previous

null response

ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV

ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV

ABT-450/RTV 100/100 mg + ABT-267 + ABT-333 + RBV

ABT-450/RTV 150/100 mg + ABT-267 + ABT-333 + RBV

93.3

NR

(n = 79)

(n = 80)

(n = 43)

(n = 45)

Future Role of Interferon

What role may interferon play in future regimens?

– Preventing resistance?

For which sets of patients may IFN play a role?

– Patients with cirrhosis?

– Treatment-experienced patients?

– Patients with resistance to DAAs?

Will newer IFNs replace currently available agents?

– EMERGE: IFN lambda may have comparable efficacy but fewer hematologic AEs vs pegIFN alfa[1]

1. Muir AJ, et al. AASLD 2012. Abstract 214.

HCV: 2013-2020

PI+PEG+RBV PI2+PEG+RBV

DAA1 + DAA2 + RBV (or)DAA1 + DAA2 + DAA3 + RBV

QUAD: PEG/RBV/DAA1/DAA2 (???)

2011 2012 2013 2014 2015 2016 2017 2018 2019 2020

PEG/RBV 0

10

20

30

40

50

60

70

80

90

100

% o

f Pati

ents