An Updated Review of Management Strategies for the HCV Nonresponder Discussion and Interactive Case Series Infergen ® Speaker Program 2008 Please see Important

An Updated Review of Management Strategies for the HCV

NonresponderDiscussion and Interactive Case Series

Infergen® Speaker Program 2008

Please see Important Safety Information including boxed warning in this presentation as well as complete Prescribing Information included on disk.

Outline

An Updated Review of Management Strategies for the HCV Nonresponder Infergen®, a Different Interferon Watch and Wait Future Therapies Peg Retreatment Double Dose Extending Therapy Maintenance Therapy

Interactive Case Discussion

Management Strategies for the HCV Nonresponder:

Infergen®, A Different Interferon

Standard of Care: Naïve HCV Genotype 1 Patients (SVR)

Pegasys® [package insert]. Nutley, NJ: Hoffman-La Roche Inc; 2005.

PEG-Intron® [package insert]. Kenilworth, NJ: Schering-Plough Corporation; 2005.

41%33%

0

20

40

60

80

100

44%36%

0

20

40

60

80

100

SV

R (

%)

PegIFN -2a 180 g + 1000-1200 mg/RBV

SV

R (

%)

PegIFN -2b 1.5 g/kg + 800 mg/RBV

IFN α2b+RBVIFN α2b+RBV

PegIFN + RBV Response Rates in HCV Populations

African Americangenotype 1

0

10

20

30

40

50

60

All Genotypes Genotype 1 HIV/HCV HIV/HCVgenotype 1

52%-53%

41%-44%27%-40%

17%-29%19%-26%

SV

R (

%)

Torriani FJ, et al. N Engl J Med. 2004;351:438-450. Jeffers LJ, et al. Hepatology. 2004;39:1702-1708.Carrat F, et al. JAMA. 2004;292:2839-2848.Muir AJ, et al. N Engl J Med. 2004;350:2265-2271.Fried MW, et al. N Engl J Med. 2002;347:975-982.

Manns MP, et al. Lancet. 2001;358:958-965.Poynard T et al. J Hepatol. 2005:42(Suppl 2):40-41.Shiffman M.L., et al. Gastroenterology 2004; 126:1015-1023.Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007.

IFN+RBV and Peg Non-Responders

2%-15%

Retreatment

Naive

Treat With a Different Interferon: Infergen® (CIFN)

CIFN=consensus interferon; SC=subcutaneous; TIW=three times per week.

Generic name: Interferon alfacon-1

Formulation: Solution for injection

Indication: Infergen® is indicated for the treatment of chronic HCV infection in patients 18 years of age or older with compensated liver disease who have anti-HCVserum antibodies and/or the presence of HCV RNA

FDA Approved Dose: 9 g SC TIW for 24 weeks for naïves. 15 g SC TIW for 48 weeks for patients not responding or relapsing to previous IFN therapy

Infergen®: A Bio-optimized Type 1 IFN

Amino acid 1 2 3 4 5 6 7position

IFN- a gly asn gly phe leu lys asn

IFN- b thr gly val phe his lys asn

IFN- d trp asn leu asn leu glu leu

IFN- f trp phe gly gly leu lys leu

IFN- g trp asn gly asn his glu his

IFN- j gln gly val phe leu lys asn

Infergen® trp asn gly phe leu lys asn

Korn AP, et al. J Interferon Res. 1994:14;1-9.

IFN-2a S L R S K EIFN-2b S L R S K ECIFN R L R R K E

Differences Among Approved IFNs


IFN-2a C D L P Q T H S L G S R R T L M L L A Q M R K I S L F S C L K D R H D F G F P QIFN-2b C D L P Q T H S L G S R R T L M L L A Q M R R I S L F S C L K D R H D F G F P QCIFN- C D L P Q T H S L G N R R A L I L L A Q M R R I S P F S C L K D R H D F G F P Q

IFN-2a R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q EIFN-2b R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q ECIFN- K K Y F Q R I T L Y L T E K K Y S P C A W E V V R A E I M R S F S L S T N L Q E

IFN-2a E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E T

IFN-2b E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E TCIFN- E E F D G N Q F Q K A Q A I S V L H E M I Q Q T F N L F S T K D S S A A W D E S

High-affinity receptor-recognition sites

Another receptor-recognition site

IFN-2a L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A VIFN-2b L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A VCIFN- L L E K F Y T E L Y Q Q L N D L E A C V I Q E V G V E E T P L M N V D S I L A V

1 amino acid difference between IFN -2a and IFN -2b19 amino acid difference between IFN -2a and CIFN18 amino acid difference between IFN -2b and CIFN

2.5 x 109

IFN -2b

Comparison of Antiviral Activity In Vitro

CIFN IFN -2a

VSVHeLaME-180

HSV

VSV=vesicular stomatitis virus; HSV=herpes simplex virus.

Blatt LM, et al. J Interferon Cytokine Res. 1996;16:489-499.

2.0 x 1010

2.5 x 109

2.0 x 1010

1.8 x 108

1.8 x 108

1.8 x 108

1.8 x 108

2.5 x 108

2.5 x 1082.5 x 108

1.8 x 108

HeLaME-180

Correlation between in vitro activity and clinical activity of any IFN is unknown

Strength of Receptor Binding

Type 1 IFN Receptor kd (M)

IFN -2b 1.07 x 10-11

CIFN 3.90 x 10-12

JAK-STAT=Janus kinase signal transduction activator of transcription.

Klein SB, et al. J Interferon Cytokine Res. 1996;16:1-6.

CIFN binds to the type 1 IFN receptor with 10-fold higher affinity when compared with IFN -2b.

ISGs: Enhanced

CIFN

Enhanced magnitude of JAK-STAT signaling

0

20

40

60

80

100

0.0 0.2 0.4 0.6 0.8 1.0 1.2

Inh

ibit

ion

of

cell

gro

wth

(%

)

IFN concentration (g/mL)

IFN -2a and IFN -2b

Comparison of Antiproliferative Effects of IFNs in Vitro

CIFN

Ozes ON, et al. J Interferon Res. 1992;12:55-59.

Infergen® Initial Registration Studies

Tong MJ, et al. Hepatology. 1997;26:747-754.

Heathcote EJ, et al. Hepatology. 1998;27:1136-1143.

Observe24 weeks

48 weeks

24 weeks

Relapsers

Nonresponders

337 patients704 patients

Responders

RetreatInfergen®

15 g TIW

Observe24 weeks

Treat 24 weeks

IFN -2b (3 MIU TIW)

Infergen® (9 g TIW)

Infergen® Has Significant Reduction in Mean Viral Load vs IFN a-2b

Note: 3 MIU15 g.


HC

V R

NA

(co

pie

s/m

L)

0-12 12 24 36 48

10,000,000

1,000,000

100,000

10,000

Study week

IFN -2b 3 MIU TIW Infergen® 9 g TIW

Baseline Treatment Period Observation Period

P<0.01

0

10

20

30

ETR SVR

24%*

15%

8%

4%

Pat

ien

ts (

%)

IFN -2b 3 MIU TIW

Infergen® 9 g TIW

Note: 3 MIU15 g.


Responses in Genotype 1 Naïve Patients Treated for 24 Weeks

P=0.04



Infergen® in IFN α-2b Nonresponders

704 patients

Observe24 weeks

Treat 24 weeks

IFN -2b (3 MIU TIW)

Retreatment

Observe24 weeks

48 weeks

24 weeks

Relapsers

Nonresponders

337 patients

Responders

RetreatInfergen®

15 g TIW

Infergen® (9 g TIW)

SVR in IFN α-2b Nonresponders

0

10

20

ETR SVR

Infergen® 15 g TIW

17%

12%

48 Weeks Retreatment

Pat

ien

ts H

CV

RN

A

neg

ativ

e (%

)


Infergen® [package insert]; Costa Mesa, CA: VPNA 2006.

Laboratory Infergen Infergen Infergen Adverse 9 g TIW 15 g TIW 15 g TIWEvents 24 Weeks 24 Weeks 48 Weeks

ANC <1000 8% 19% 24%

ANC <500 1% 1% 0%

Platelets <50,000 3% 5% 3%

Platelets <25,000 1% 0% 0%

Laboratory Adverse Events With Infergen® Use: Hematologic Side Effects

ANC=absolute neutrophil count.




Dropouts due to adverse events 7% 7% 5% 11%

Dosereductions 16% 12% 33% 36%

Initial Treatment Retreatment

Infergen® IFN -2b Infergen Infergen9 g TIW 3 MIU TIW 15 g TIW 15 g TIW24 Weeks 24 Weeks 24 Weeks 48 Weeks

Safety


Watch and Wait

HCV Patient Projections

Decision Resources Hepatitis C Report & Interactive Forecast Tool 2005.

Future Disease Burden: Estimated Increase From 2000 to 2020

HCC=hepatocellular carcinoma.

Davis GL, et al. Liver Transpl. 2003;9:331-338.

106%

180%

81%

100%

0

50

100

150

200

Cirrhosis HCC Liver-related deaths

Liver decompensation

Incr

ease

(%

)

Adapted from: Fattovich G et al. Gastroenterology. 1997;112:463-472.

Natural History of HCV Cirrhosis

100

80

60

40

20

0

Time (years after diagnosis)

After 1st complication

Su

rvi v

al p

rob

abil

i ty

(%)

Compensated

1 2 3 4 5 6 7 8 9 100

DeathsLiver-related (70%)Other causes (30%)

Waitlist and Liver Transplant Activity: 1995-2004

OPTN/SRTR Annual Report: Table 1.3, 1.7,1.6.

Nu

mb

er o

f P

atie

nts

HCV is the most common indication for OLT accounting for 40%–50% of both individuals on the waiting list and those who have undergone liver transplants

Shiffman M.L., et al. Gastroenterology 2004; 126:1015-1023.

Effect of Cirrhosis on SVR in IFN+RBV Retreatment: Halt-C Lead-In Phase

HC

V R

NA

neg

ativ

e (%

)

37%

23%23%

11%

0

20

40

60

80

48 Weeks SVR

F3 Fibrosis

F4 Cirrhosis

Predicted Impact of Age on SVR

Adapted from: Foster G, et al. AASLD; October 24–28, 2003. Boston, MA. Abstract 189.

0

10

20

30

40

50

60

70

80

90

Cal

cula

ted

SV

R (

%)

553025 4035 504520 60

Age (completed life-years)

0 302010 400

0.25

1.00

0.75

0.50

Duration (y)

Pro

bab

ility

of

de

velo

pin

g c

irrh

osi

s

Age >50

Age 41-50

Age 31-40

Age 21-30

Age <21

Marcellin P, et al. Hepatology. 2002;36:S47-S56.

Progression to Cirrhosis Becomes Nonlinear with Age


Future Therapies

New Therapies Will Not Be On the Market for the Next Several Years

100%

71%

21%

21%

32%

0

20

40

60

80

100

Preclinical Phase I-II Phase II-III Phase III-market

FDAapproval

1 Year 3 Years 3 Years

DiMasi JA, et al. J Health Econ. 2003;22:151-185.

Ad

van

cin

g t

o

the

nex

t p

has

e (%

)

1 Year

Timeline for New Therapies in Development

ITMN 191Protease Inhibitor

BLX-883Locetron Interferon

R1626Polymerase Inhibitor

SCH 503034Protease Inhibitor

VX-950Protease Inhibitor

TaribavirinRBV Pro Drug

Phase 1 Phase 2 Phase 3

FDA REVIEW

http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008

Franciscus A. Hepatitis C Support Project. Dec. 28, 2006.

1 Year 2-3 Years 2-3 Years

AlbuferonInterferon Albumin

BavituximabAnti phospholipid

GS-9190Polymerase Inhibitor

R7128Polymerase Inhibitor

TMC435350Protease Inhibitor

VCH-759 Polymerase inhibitor

GSK625433Polymerase inhibitor

BLX-883Locetron Interferon

Discontinued Clinical Programs

COMPANY PRODUCT PHASEREASON FOR

DISCONTINUATIONDESCRIPTION

Roche/Ribapharm

Levovirin Phase I Lack of activity and formulation issues

L-isomer of RBV

Boehringer Ingelheim

BILN 2061 Phase II Cardiac toxicity in animals Protease inhibitor

Vertex Pharmaceutical

Merimepodib (MMPD)

Phase II Lack of efficacy Polymerase inhibitor

Maxim Pharmaceuticals

Maxamine® Phase III Lack of efficacy Immune response modifier

Indevus IP 501 Phase III Unknown Antifibrotic

Coley Pharmaceutical

ACTILON (CPG 10101)

Phase I/II Lack of efficacy Toll-like receptor agonist

Achillion/Gilead ACH806 Phase II Safety Protease Inhibitor

Idenix/NovartisValopicitabineNM283

Phase IIClinical development on hold per FDA request for safety reasons

Polymerase Inhibitor

Anadys / Novartis ANA 975 Phase Ib Safety Toll-like receptor agonist

http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008

Management Strategies for the HCV Nonresponder: Peg Retreatment

AASLD Treatment Guidelines

“Retreatment with peginterferon plus ribavirin with the aim of eradicating HCV is not indicated in patients who have failed to respond to a prior course of peginterferon plus ribavirin, even if a different type of peginterferon is administered (Grade III).”

AASLD=American Association for the Study of Liver Diseases.

Strader DB, et al. Hepatology. 2004;39:1147-1171.

IFN-2a E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E TIFN-2b E E F G N Q F Q K A E T I P V L H E M I Q Q I F N L F S T K D S S A A W D E T

IFN-2a L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A VIFN-2b L L D K F Y T E L Y Q Q L N D L E A C V I Q G V G V T E T P L M K E D S I L A V

IFN-2a R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q EIFN-2b R K Y F Q R I T L Y L K E K K Y S P C A W E V V R A E I M R S F S L S T N L Q E

IFN-2a S L R S K EIFN-2b S L R S K E

IFN-2a C D L P Q T H S L G S R R T L M L L A Q M R K I S L F S C L K D R H D F G F P QIFN-2b C D L P Q T H S L G S R R T L M L L A Q M R R I S L F S C L K D R H D F G F P Q

There is 1 amino acid difference between IFN -2a and IFN -2b

Differences Among IFN -2a and IFN -2b


Retreatment of IFN + RBV Failures With PEG-IFN + RBV

Retreatment of IFN + RBV Failures With PEG-IFN + RBV

Investigator N Study Drug/Dose SVR

Teuber G, et al. DDW. 2003 240PEG-IFN α-2b 100 g + RBV 800 mg x 8 wk

PEG-IFN α-2b 50 g + RBV 800 mg x 40 wk6.3%

Jacobson I, et al. DDW. 2003 219PEG-IFN α-2b 1.0 g/kg + RBV 1–1.2 g x 48 wk

PEG-IFN α-2b 1.5 g/kg + RBV 800 mg x 48 wk

6%

10%

Sulkowski M, et al. DDW. 2003 517PEG-IFN α-2b 1.5 g/kg + RBV 800 mg x 48 wk

PEG-IFN α-2b 100/150 g + RBV 800 mg x 48 wk12%

Lawitz E, et al. DDW. 2003. 486PEG-IFN α-2b 1.5 g/kg + RBV 1–1.2 g x 12 wk

PEG-IFN α-2b 1.0 g/kg + RBV 800 mg x 36/48 wk5–10%

Shiffman ML, et al. Gastroenterology. 2004

210 PEG-IFN α-2a 180 g + RBV 1–1.2 g x 48 wk 12%

Poynard T, et al. EASL. 2005 978 PEG-IFN α-2b 1.5 g/kg + RBV 0.8–1.4 g x 48 wk 14%

Gaglio P, et al. AASLD. 2005 454PEG-IFN α-2b 1.5 g/kg/wk + RBV 800-1400 mg/d

x 48 wks14%

Gross JB, et al. AASLD. 2005 764PEG-IFN α-2b 0.5/1.5/3.0 g/kg + RBV 12–15 mg/kg

x 48 wk12-

17%

Teuber G, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1216. Jacobson IM, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract 504.Sulkowski M, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1292. Lawitz EJ, et al. DDW May 17–22, 2003; Orlando, FL. Abstract T1293. Shiffman ML, et al. Gastroenterology. 2004;126:1015-1023.

Poynard T, et al. EASL; April 13–17, 2005; Paris, France. Abstract 96. Gaglio P, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 59.Gross JB, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 60.

Retreatment of PEG-IFN + RBV Failures With PEG-IFN + RBV

Retreatment of PEG-IFN + RBV Failures With PEG-IFN + RBV

Investigator N Study Drug/Dose SVR

Afdhal N, et al.

EASL 2007178

PEG-IFN α-2a180 g QW + RBV (1–1.2 g/day) x 48 wks

3%

Schiff E, et al. 357PEG-IFN α-2b 1.5g/kg QW + RBV (800-1400mg/day) x 48 wks

2%

Afdhal N et al. Hepatol . 2007: 46 (Suppl S5).Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007.

Management Strategies for the HCV Nonresponder: Double Dose Peg

To evaluate the efficacy, safety, and tolerability of PEG-IFN -2b + weight-based RBV in prior IFN + RBV nonresponders

PEG-IFN -2b: 1.5 g/kg/week, 3.0 g/kg/week

RBV: 12-15 mg/kg/d

Stratified for sex, race, genotype, and fibrosis

963 patients enrolled in study

Including152 African Americans, of these:

66 received 1.5 g/kg (11 did not start treatment)

64 received 3.0 g/kg (6 did not start treatment)

22 received 0.5 g/kg, this arm was discontinued

RENEW Trial: Study Aim

Gross et al. AASLD 2005; San Francisco, CA. Oral Session 60.

48 Weeks

SVR

Results

RBV --------------------- 12-15 mg/kg/d ---------------------------------------Discontinuation 32% 35% 36%

4% 12%17%

0

20

40

60

80

100

0.5 g/kg/week PEG-IFN

1.5 g/kg/week PEG-IFN

HC

V R

NA

neg

ativ

e (%

)

P=NS

N=704

3 g/kg/week PEG-IFN

Gross et al. AASLD 2005; San Francisco, CA. Oral Session 60.

24% 24%17%

Follow-up

REPEAT Trial: Study Design

A

B

C

D Follow-up

Follow-up

Follow-up

PEG-IFN -2a180 µg

plus RBV 1000-1200mg

PEG-IFN -2a180 µg

PEG-IFN -2a180 µg

PEG-IFN -2a180 µg


360 µg

360 µg

0 12 24 36 48 60 72 84 96

Study Week

942 patients randomized 2:1:1:2

Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4.



Patient Demographics

PEG-2a + RBVA (n=317)

360/180mcg/w (72w)

B (n=156) 360/180mcg/w

(48w)

C (n=156) 180mcg/w

(72w)

D (n=313) 180mcg/w

(48w)

Male (%) 64 60 69 68

Mean age+SD (y) 48.1+8.7 48.8+9.9 49.4+8.5 48.5+9.0

Mean weight+ SD (kg) 81.5+18.2 81.1+16.8 81.2+16 80.9+16.9

Caucasian (%) 88 90 88 90

G1 (%) 91 91 91 91

Cirrhosis (%) 25 29 30 28

Mean+SD baseline HCV RNA (x106

IU/ML)5.4+6.4 5.3+7.1 4.9+5.1 4.9+6.0


Safety


PEG-2a + RBVA (n=317)

360/180mcg/w (72w)

B (n=156) 360/180mcg/w

(48w)

C (n=156) 180mcg/w

(72w)

D (n=313) 180mcg/w

(48w)

Premature d/c for safety n (%) 37 (12%) 7 (4%) 18 (12%) 20 (6%)

Patients with serious adverse

events n (%)33 (10%) 14 (9%) 28 (18%) 33 (11%)

Overall Hematological 5 (2%) - 3 (2%) 6 (2%)

Peg dose modifications n (%) 72 (23%) 41 (26%) 36 (23%) 57 (18%)

Results

360/180 μg/wk 180 μg/wk

SVR in pooled 72-wk vs 48 wk arms: 16% vs 8% (P = .0006; OR: 2.22; 95% CI: 1.40-3.52)

PP Analysis

31 33 31 28

52

78

64 68

0

20

40

60

80

100

72 wk (n=317) 48 wk (n=156) 72 wk (n=156) 48 wk (n=313)

Per

cen

t, %

ETR Relapse SVR

716 14 9


Management Strategies for the HCV Nonresponder: Extending Therapy

Study Design

Berg T, et al. Gastroenterology. 2006;130:1086-1097.

Week 0 Week 48Weeks 12-24 Week 72

Berg (n=455)PegIFN -2a 180mcg QW +RBV 800 mg

Treatment Naive G1 only

48 weeks

72 weeks

n=230

n=225

Overall Results

63%

53% 54%

71%

Per

cen

t, %

EOT 48 Weeks

SVR 48 Weeks

SVR 72 Weeks


SVR by Viral Response Time Points in Treatment Naïve G1 Patients

“Note that only 1 patient in each group (2/455 – 0.4%) with HCV-RNA Levels greater than 6,000 IU/mL (12 weeks) achieved an SVR.”


Discontinuation Rates

Treatment Arm

Treatment Discontinuatio

n

Group A (48 Weeks) 24%

Group B (72 Weeks) 41%


Results and Conclusions

Overall, no significant differences could be observed in the treatment outcome in both groups (53% vs. 54%)

Patients with undetectable HCV-RNA levels at week 4 and 12 had excellent SVR rates ranging form 76% to 84% regardless of treatment groups

Patients shown to be still HCV-RNA positive at week 12 achieved significantly higher SVR rates when treated for 72 vs 48 weeks (29% vs. 17% P=0.04) A particular benefit from extended treatment duration was seen in

patients with low level viremia (<6000IU/mL at week 12)

Extended treatment duration generally is not recommended in HCV G1 infection and should be reserved only for patients with slow virologic response defined as HCV RNA positive at week 12 but negative at week 24



Maintenance Therapy

PrimaryGoal

The Goals of Treatment

SecondaryGoal

Eradicate HCV infection

Slow disease progression

Improve histology

Reduce risk of HCC

Sethi A, et al. Clin Liver Dis. 2005;9:453-471.

HALT-C Final Results

Low dose peginterferon alfa-2a arm (90 µg/week) vs control group had Greater reductions in HCV RNA and ALT (P < .0001) Greater reductions in necroinflammation (P < .001)

No reduction in fibrosis or difference between arms No significant difference between arms in any primary outcome 34.1% vs 33.8%: HR 1.01 (95% CI, 0.81-1.26)

Di Bisceglie A, et al. AASLD 2007. Abstract LB1.

Study Arm Baseline Fibrosis*

Any primary outcome, %

Death, % HCC, % CTP score ≥ 7, %

Peginterferon alfa-2a90 µg/week (n = 517)

3/4 36.6 2.6 2.6 3.2

5/6 30.1 2.4 1.9 17.8

Control (n = 533)3/4 35.5 0.6 1.6 3.2

5/6 31.1 2.7 4.6 14.6

*Ishak Score

Impact of SVR on Fibrosis

Shiratori Y, et al. Ann Intern Med. 2000;132:517-524.

3 Years Post Therapy

Patients

0.59

0.15

-0.6Untreated No SVR SVR

IFN-treated

0.6

0.3

-0.3

-0.6

0

Ch

ang

e in

fib

rosi

s st

age

Summary

The primary goal of therapy is to eliminate the virus

Only 50% of naïve patients and 30% of difficult-to-treat naïve patients achieve SVR

The nonresponder patient population is growing

Infergen® is a unique, bioengineered IFN

Treating younger patients and earlier during the disease progression timeline can translate to more successful outcomes

It will be several years until new drugs enter the HCV marketplace, and interferon will always play a role

Interactive Case Discussion

Positive Predictive Factors for Achieving SVR

• Viral Factors Non-1 genotype (2/3) Lower HCV RNA level Early virologic response

Disease-Related Factors Absence of advanced fibrosis Lack of steatosis

• Appropriate RBV dosage

• Host Factors Lower body weight Younger age Female gender Race (non-AA)

• Adherence More than 80% of

intended treatment for more than 80% of intended duration

Ferenci P. Semin Liver Dis. 2004;24(suppl 2):25-31.

SustainedResponder

Null ResponderRelapserRelapser

Partial Responder

HCV RNAnegative

Time (weeks)

HCV RNA

12 (EVR)

24 48 (EOT)

72 (SVR)

Patient Profiles During HCV Therapy

Adapted from:Davis GL, et al. Hepatology. 2003;38:645-652.Fried MW, et al. N Engl J Med. 2002;347:975-982. Sanchez-Tapias JM. Gastroenterology 2006;131:451-460

4(RVR)

RVR = HCV RNA (-) at week 4EVR = ≥2log10 drop in HCV RNA or HCV RNA (-) at week 12 EOT = HCV RNA (-) at week 48 (genotype 1)SVR = HCV RNA (-) 24 weeks post treatment cessation

Treatment Duration: Positive and Negative Predictor Algorithms

PEG-IFN -2a/RBVWeek 12(n=453)

2-log drop orundetectable HCV RNA

86%(n=390)

14%(n=63)

Yes

No

Fried MW, et al. N Engl J Med. 2002;347:975-982.

65%(n=253)

35%(n=137)

3%(n=2)

97% (n=61)

SVR

No SVR

SVR

No SVR

Berg TA et al. Hepatology 2006;130:1086-1097

Treatment Naïve Patients – Genotype 1

SV

R b

y V

iral

Res

po

nse

Tim

e P

oin

ts (

%)


Sensitive Testing Can Affect Your Treatment Duration Decisions:

TMA Positive Results from PCR-negative Samples – HALT-C

Morishima C et al. Hepatology 2006;44:360-367.

PCR – Roche COBAS Amplicor, Lower Limit of Detection 100 IU/mL

22%

37%

27%20%

Week 12

% T

MA

po

siti

ve

n=1294 n=241 n=373 n=361n=319

0

20

40

60

80

Overall Week 20 Week 24 Week 48

6%

The increased sensitivity offered by TMA testing may detect treatment failures earlier

22% of the patients who are PCR negative by Roche Amplicor are positive by TMA

Patients who are negative by Roche Amplicor at week 20 but positive by TMA had a 0% SVR

HCV Treatment Algorithm

* For information on early response for patient management purposes only; not a decision point in the protocol.**Patients should be maintained on treatment for 36-48 weeks from the first negative TMA test.www.point-of-hcv-care.com Barnett K. Review Paper

Testing

Quantitative

Qualitative (TMA)

End treatment

24-week follow-up

12 weeks

<2 log drop or +

HCV RNA

continue

therapy

24 weeks

≥48 weeks**

RELAPSER SVR

Negative or ≥2 log dropHCV RNA

HCV RNA

positive

HCV RNAnegative

HCV RNApositive

HCV RNAnegative

y×10z y×10z

Baseline

y×10z y×10z

+ –4 weeks*

y×10z y×10z

continue

therapy

continue

therapy

y×10z y×10z

HCV RNA

positive

+ –

+ –

+ –

+ –

HCV RNAnegative

Consider Alternative Treatment Options

Case 1- RVR

40 year old

Male

Caucasian

G1

Viral Load- 350,000 IU/mL

F2

91kg

Initiated on peginterferon alpha-2a 180mcg QW and ribavirin 1200mg

Week 4 HCV RNA – Negative

• Identify this patient’s positive vs. negative predictors for success?

• What strategies could you implement to optimize outcomes in this patient?

• What is this patient’s chance of SVR if he remains on Peg therapy for 48 wks?

Predictive Factors for SVR

Positive

Younger Age

Caucasian

Low Viral Load

F2

RVR

Negative

Male

Genotype 1

Heavier Weight




Case 2- EVR Week 12 Negative

52 year old

Female

Caucasian

G1


F2

60kg


Week 4 HCV RNA – 450,000 IU/ML

Week 12 HCV RNA- Negative



• What is this patient’s chance of SVR if she remains on Peg therapy for 48 wks?


Positive

Female

Caucasian

F2

Lower body weight

EVR

Negative

Older Age

Genotype 1

High Viral Load




Case 3- EVR Week 12 Positive

35 year old

Male

Caucasian

G1

Viral Load- 1,800,000 IU/mL

F3

68kg


Week 4 HCV RNA- 180,000 IU/ML




• What is this patient’s chance of SVR if he remains on Peg therapy for 48 wks?

• What other options could you consider in the treatment of this patient?


Positive

Younger Age

Caucasian

Lower Body Weight

EVR

Negative

Male

G1

High Viral Load

F3


SVR by Viral Response Time Points in Treatment Naïve Patients – Genotype 1

Case 4- Nonresponder

68 year old

Female

African American

G1

Viral Load- 2,500,000 IU/mL

F3

63kg

Initiated on peginterferon alpha-2b 1.5mcg/kg QW and ribavirin 800 mg

Week 4 HCV RNA- 2,000,000 IU/ML

Week 12 HCV RNA- 1,000,000 IU/ML

• Identify this patient’s positive vs. negative predictors for success?• The clinician discontinued therapy in this patient at week 12 due to nonresponse. Do you

agree with this decision?• What strategies could you have implemented to optimize outcomes in this patient?• How would you manage this patient at this point?


Positive

Female

Lower body weight

Negative

Older Age

African American

G1

High Viral Load

F3

Negative Predictors of Response

PEG-IFN -2a/RBVWeek 12(n=453)

2-log drop orundetectable HCV RNA

86%(n=390)

14%(n=63)

Yes

No

Fried MW, et al. N Engl J Med. 2002;347:975-982.

65%(n=253)

35%(n=137)

3%(n=2)

97% (n=61)

SVR

No SVR

SVR

No SVR

Case 5- Relapser

42 year old

Male

Caucasian

G1


F2

85kg

Initiated on peginterferon alpha-2a 180mcg QW and ribavirin 1200 mg



Week 24 HCV RNA- Negative

Week 48 HCV RNA- Negative- STOPPED THERAPY

Week 72 HCV RNA- 1000 IU/ML

• Identify this patient’s positive vs. negative predictors for success?• What strategies could you have implemented to optimize outcomes in this patient?• What options would you offer your patient at this point?


Positive

Younger Age

Caucasian

F2

Negative

Male

G1

High Viral Load

Higher Body Weight

SustainedResponder

Null ResponderRelapserRelapser

Partial Responder

HCV RNAnegative

Time (weeks)

HCV RNA

12 (EVR)

24 48 (EOT)

72 (SVR)

Patient Profiles During HCV Therapy

Adapted from:Davis GL, et al. Hepatology. 2003;38:645-652.Fried MW, et al. N Engl J Med. 2002;347:975-982. Sanchez-Tapias JM. Gastroenterology 2006;131:451-460

4(RVR)

RVR = HCV RNA (-) at week 4EVR = ≥2log10 drop in HCV RNA or HCV RNA (-) at week 12 EOT = HCV RNA (-) at week 48 (genotype 1)SVR = HCV RNA (-) 24 weeks post treatment cessation

References

Afdhal N et al. Hepatol . 2007: 46 (Suppl S5).Berg TA, et al. Hepatology 2006;130:1086-1097.Blatt LM, et al. J Interferon Cytokine Res. 1996;16:489-499.Boceprevir Update Press Release; Schering Plough Pharmaceuticals; Kenilworth, NJ: Oct 18, 2007.Carrat F, et al. JAMA. 2004;292:2839-2848.Davis GL, et al. Hepatology. 2003;38:645-652.Davis GL, et al. Liver Transpl. 2003;9:331-338.Decision Resources Hepatitis C report 2005.Di Bisceglie A, et al. AASLD 2007. Abstract LB1.DiMasi JA, et al. J Health Econ. 2003;22:151-185. Fattovich G et al. Gastroenterology. 1997;112:463-472.Ferenci P. Semin Liver Dis. 2004;24(suppl 2):25-31.Foster G, et al. AASLD; October 24–28, 2003. Boston, MA. Abstract 189.Franciscus A, Hepatitis C Support Project. Dec. 28, 2006. Fried MW, et al. N Engl J Med. 2002;347:975-982.Gaglio P, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 59.Gross JB, et al. AASLD; Nov 11–15, 2005; San Francisco, CA. Abstract 60.Healthcote EJ, et al. Heptatology. 1998;27:1136-1143.Infergen® [package insert]. Costa Mesa, CA: VPNA, 2006Jacobson IM, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract 504.Jeffers LJ, et al. Hepatology. 2004;39:1702-1708. Jensen D, et al. AASLD 2007; San Francisco, CA. Abstract LB4. Klein SB, et al. J Interferon Cytokine Res. 1996;16:1-6.

References (cont’d)

Korn AP, et al. J Interferon Res. 1994;14:1-9.Lawitz EJ, et al. DDW May 17–22, 2003; Orlando, FL. Abstract T1293. Manns MP, et al. Lancet. 2001;358:958-965.Marcellin P, et al. Hepatology. 2002;36:S47-S56.Morishima C, et al. Hepatology 2006;44:360-367.Muir AJ, et al. N Engl J Med. 2004;350:2265-2271.

OPTN/SRTR Annual Report: Table 1.3, 1.7,1.6.

Ozes ON, et al. J Interferon Res. 1992;12:55-59.

Pegasys® [package insert]. Nutley, NJ: Hoffman-La Roche Inc; 2005.

PEG-Intron® [package insert]. Kenilworth, NJ: Schering-Plough Corporation; 2005.

Poynard T, et al J Hepatol. 2005:42(Suppl 2):40-41.

Poynard T, et al. Abstract presented at: EASL, 2005; Paris, France. Abstract 96.

Sanchez-Tapias JM, Gastroenterology 2006;131:451-460.

Sethi A, et al. Clin Liver Dis. 2005;9:453-471.

Shiffman ML, et al. Gastroenterology. 2004;126:1015-1023.

Shiratori Y, et al. Ann Intern Med. 2000;132:517-524.

Strader, et al. Hepatology. 2004; 39 (4):1157-1171.

Sulkowski M, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1292.

Teuber G, et al. DDW; May 17–22, 2003; Orlando, FL. Abstract T1216.

Torriani FJ, et al. N Engl J Med. 2004;351:438-450.

Tong MJ, et al. Hepatology.1997;26:747-754.

http://www.hcvadvocate.org/hepatitis/hepC/hcvdrugs.html. Accessed January 2008.

Please see the Important Safety Information, including boxed warning, as well as the complete prescribing information included on the CD-Rom Disk.

Copyright © Three Rivers Pharmaceuticals 2008. All Rights Reserved. INFERGEN is a registered Trademark of Amgen, Inc. and Three Rivers Pharmaceuticals is the exclusive licensee from Amgen of this mark.

INFERGEN® is indicated for the treatment of chronic HCV infection in patients 18 years of age or older with compensated liver disease who have anti-HCV serum antibodies and/or the presence of HCV RNA. Other causes of hepatitis, such as viral hepatitis B or autoimmune hepatitis, should be ruled out prior to initiation of therapy with INFERGEN®. The most commonly reported adverse events during initial and subsequent treatment were headache, fatigue, fever, myalgia, rigors, body pain, arthralgia, and nausea.

Important safety information:

Alpha interferons, including Interferon alfacon-1, cause or aggravate fatal or life-threatening neuropsychiatric, autoimmune, ischemic, and infectious disorders. Patients should be monitored closely with periodic clinical and laboratory evaluations. Patients with persistently severe or worsening symptoms of these conditions should be withdrawn from therapy. In many but not all cases, these disorders resolve after stopping Interferon alfacon-1 therapy.See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS and ADVERSE REACTIONS in full prescribing information.

INFERGEN® is contraindicated in patients with known hypersensitivity to alpha interferons or to any component of the product, in patients with decompensated hepatic disease and autoimmune hepatitis. Development of or exacerbation of autoimmune disorders (e.g. autoimmune thrombocytopenia, idiopathic thrombocytopenic purpura, psoriasis, rheumatoid arthritis) have been reported in patients receiving alpha interferon therapies, including INFERGEN.

Treatment with INFERGEN should be administered under the guidance of a qualified physician, and may lead to moderate-to-severe adverse experiences requiring dose reduction, temporary dose cessation, or discontinuation of further therapy.

Severe psychiatric adverse events may manifest in patients receiving therapy with alpha interferons, including INFERGEN. Depression, suicidal ideation, suicide attempt, and suicide may occur. Other prominent psychiatric adverse events may also occur, including psychosis, aggressive behavior, nervousness, anxiety, emotional lability, abnormal thinking, agitation, apathy and relapse of drug addiction. INFERGEN should be used with extreme caution in patients who report a history of depression. Physicians should monitor all patients for evidence of depression and other psychiatric symptoms. In severe cases, therapy should be stopped immediately and psychiatric intervention instituted.

Bone Marrow Toxicity: Alpha interferons suppress bone marrow function and may result in severe cytopenias including very rare events of aplastic anemia. It is advised that complete blood counts be obtained pretreatment and monitored routinely during therapy. Alpha interferon therapy should be discontinued in patients who develop severe decreases in neutrophil (<0.5 x 109/L) or platelet counts (<50 x 109/L).

Hypertension, tachycardia, palpitation, and tachyarrythmias have been reported in patients treated with INFERGEN. INFERGEN should be administered with caution to patients with preexisting cardiac disease. Supraventricular arrhythmias, chest pain, and myocardial infarction have been associated with alpha interferon therapies.Pneumonia and interstitial pneumonitis, some resulting in respiratory failure and/or patient deaths, have been induced or aggravated by alpha interferon therapy, including INFERGEN. Patients who develop persistent or unexplained pulmonary infiltrates or pulmonary function impairment should discontinue treatment with INFERGEN.Chronic hepatitis C patients with cirrhosis may be at risk of hepatic decompensation when treated with alpha interferons, including INFERGEN. During treatment, patients' clinical status and hepatic function should be closely monitored, and INFERGEN treatment should be immediately discontinued if symptoms of hepatic decompensation, such as jaundice, ascites, coagulopathy, or decreased serum albumin, are observed.

Ophthalmologic Disorders: Decrease or loss of vision, retinopathy including macular edema, retinal artery or vein thrombosis, retinal hemorrhages and cotton wool spots; optic neuritis, and papilledema are induced or aggravated by treatment with INFERGEN or other alpha interferons. All patients should receive an eye examination at baseline. Patients with preexisting ophthalmologic disorders (e.g., diabetic or hypertensive retinopathy) should receive periodic ophthalmologic exams during interferon alpha treatment. INFERGEN therapy should be discontinued in patients who develop new or worsening ophthalmologic disorders.

Ischemic and hemorrhagic cerebrovascular events including hemorrhagic stroke have been observed in patients being treated with INFERGEN. In addition, transient ischemic attack has been reported in young patients being treated with INFERGEN without other reported risk factors.

INFERGEN should be discontinued immediately and appropriate medical treatment instituted if hypersensitivity reactions occur. INFERGEN should be administered with caution to patients with a history of endocrine disorders and should be discontinued immediately in patients who develop signs and symptoms of colitis. In addition, INFERGEN should be suspended in patients with signs and symptoms suggestive of pancreatitis and discontinued in patients diagnosed with pancreatitis.

The most common adverse events reported for INFERGEN during clinical studies were headache (82%), fatigue (69%), fever (61%), myalgia (58%), rigors (57%), body pain (54%), arthralgia (51%), nausea (40%), insomnia (39%), pharyngitis (34%), nervousness (31%), infection upper respiratory (31%), diarrhea (29%), depression (26%), anorexia (24%), injection site erythema (23%), granulocytopenia (23%), dizziness (22%), cough (22%), dyspepsia (21%), thrombocytopenia (19%), anxiety (19%), sinusitis (17%), influenza-like symptoms (15%) and leucopenia (15%).

Please see complete Prescribing Information, including boxed warning, included on the disk.

Documents

An Updated Review of Management Strategies for the HCV Nonresponder Discussion and Interactive Case Series Infergen ® Speaker Program 2008 Please see Important