Hepatitis C Infection: Challenges and Evolving Opportunities

1
Hepatitis C Infection- Challenges and
Evolving Opportunities -

• James R. Minor, Pharm.D
• james.minor_at_gilead.com
• 919-641-2856
• 2 June 2009

2
Disclaimer
3

• Hepatitis C is one of the most significant
  preventable and treatable public health problems
  facing our nation. a graver threat than the AIDS
  crisis.

4
Self-Assessment Questions
5
The most common blood-borne chronic viral illness
in the US is

• A. Influenza
• B. Hepatitis B
• C. Hepatitis C
• D. Measles

6
The primary age group infected with HCV in the
US is

• Infants born to HCV mothers
• Adolescents, 14-18 years of age
• Adults, 35-55 years of age

7
Risk of becoming infected from a percutaneous
exposure to an HCV individual

• A. 0.3
• B. 3.0
• C. 30.0

8
The current standard of care for chronic HCV
infection is

• Recombinant SC interferon
• Pegylated SC interferon oral Ribavirin
• Tenofovir Emtricitabine
• D. Telaprevir Peg-Interferon/Ribavirin

9
The key dose-limiting toxicities of Ribavirin

• Pancytopenia
• Stevens-Johnson syndrome
• Dose-dependent hemolytic anemia
• Teratogenicity

10
HCV Worldwide Prevalence - Over 200 million
Infected -
11
Hepatitis C in the USScope of the problem in
2009

• Estimated 6,000,000 infected Americans
• Less than 150,000 treated at any given time
• 80 will die WITH their disease not FROM their
  disease
• Large untreated US and worldwide population with
  HCV

12
Hepatitis C in the USScope of the problem in
2009

• HCV is the most common blood-borne chronic viral
  illness in the US
• HCV is the leading cause of chronic liver disease
  and adult liver transplantation
• Chronic liver disease among top 10 causes of
  death for gt25 yoa, and HCV is the underlying
  cause in 40-60 of cases
• 20-30 of people with CHCV develop cirrhosis
• 1-4 of these develop liver cancer
• 10,000-20,000 deaths annually in US from HCV
  disease
• No protective vaccine unlike Hep A and B

13
Hepatitis C in the USScope of the problem in
2009

• Estimated 6 million Americans infected, 1 in 50
• Number of HCV 3-5 times greater than HIV
• 70 on HCV Americans are 35-55 years of age
• Estimated 30,000 new cases annually
• Majority are unaware, asymptomatic
• 75 of people exposed will develop chronic
  infection and sequelae fibrosis, cirrhosis, HCC
• Disproportionately affects medically underserved
  homeless, African-Americans, Native Americans,
  Hispanics, Asian/Pacific Islanders

14
Paradigm of HCV Diagnosis and Treatment
Treated1
Treated but failed1
Diagnosed but not treated1
Not diagnosed2

• Evon DM, et al. Dig Dis Sci. 200752(11)3251-3258
  .
• 2. McHutchison JG, Bacon BR. Am J Manag Care.
  200511(10 suppl)S286-S295.

15
Hepatitis C in the USScope of the problem in
2009

• Direct medical costs of HCV infection gt750
  million/year
• Total medical expenditures for people with
  chronic HCV 15 billion/year
• Employer costs for absenteeism due to HCV 5
  billion/year
• Costs of premature disability and death
  2010-2019 75 billion
• Years of productive life lost to HCV 2010-2019
  3.1 million years
• HCV infection adversely affects quality of life
  QoL

16
Hepatitis C in the US- Correctional Facilities
-

• Prevalence of HCV infection in prison inmates is
  substantially higher than in general US
  population
• Among prison inmates, 16-40 have ever been HCV,
  and 12-35 are chronically infected compared to
  1 to 1.5 in the general, un-institutionalized US
  population
• Risk factors for inmates IDU, cocaine use,
  sharing of razors, tatoos, . . .
• Inmates reporting risk factors should be tested
  for HCV if positive, they should be evaluated
  for sequelae of chronic infection, managed
  medically as appropriate

17
Hepatitis C in the USScope of the problem in
2009

• 25-30 of HIV Americans are co-infected with HCV
• HIV/HCV co-infected patients have two-fold higher
  risk of cirrhosis and six-fold higher risk of
  liver failure compared to HCV mono-infected
• HCV-related ESLD is now a leading cause of death
  in HIV persons

18
Hepatitis C in the USScope of the problem in
2009

• Without intervention, complications associated
  with HCV-related cirrhosis are projected to
  increase dramatically by 2020
• liver failure by 106
• liver cancer by 81
• liver-related deaths by 180

19
HCV The future in the USA
Davis et al. Liver Transplantation 9 4 331-338
20
Predictions Based on Aging Population of Patients
With HCV
Armstrong, GL Ann Intern Med 144705-714
21
Natural History of HCV Infection
100 (100)
HCV is a slowly progressive disease evolving
over 10 to 20 years
Acute Infection
25 (25)
75 (75)
HIV and Alcohol
Resolved
Chronic
20 (15)
80 (60)
Cirrhosis
Stable
25 (4)
75 (11)
Liver failure, HCC Transplant Death
Slowly Progressive
22
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The Impending Public Health Challenge
24
Currently Approved Therapy for HCV

• Goal of HCV therapy eradicate viral infection
• Currently approved treatment combination
  once-weekly subcutaneous Peg-IFN and daily oral
  RBV
• Indications
• PegIFN ?-2a and ?-2b are indicated for use alone
  or in combination with RBV in adults with chronic
  HCV with compensated liver disease who previously
  have not been treated with interferon-?

25
Currently Approved Therapy for HCV

• Duration of therapy ranges from 24 to 48 weeks
  based on genotype
• HCV genotype 1 predominant in US
• Genotypes 1 and 4 do not respond as well as
  genotypes 2 and 3 to current therapies
• Currently, no therapies approved for patients who
  did not achieve sustained viral response SVR on
  prior treatment

26
HCV- The Virus -
27
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28
The Hepatitis C Genome
HCV Polyprotein
NS3 Protease domain
29
Specific Targets for HCV TreatmentProtease and
Polymerase Inhibition
September 2008 ?Vertex Pharmaceuticals
Incorporated, 2008
Kwong A, et al. Drug Discov Today.
20063(2)211-220.
30
HCV Genotypes and Subtypes
Simmonds P Hepatology, 1999
31
Treatment Response Terms

• Early Virologic Response (EVR)
• Either undetectable HCV RNA or gt2 log reduction
  from pretreatment value
• End of Treatment Response (EOT)
• Undetectable HCV RNA at completion of therapy
• Sustained Virologic Response (SVR)
• Undetectable HCV RNA 6 months after therapy
  complete
• SVR Cure ??

32
Factors Affecting Response Rates

• HCV Genotype GT, GT-1 most common in US
• Delivering full doses PEG-Ifn, Ribavirin
• Ability of patient to tolerate treatment
• Patient adherence and completion of full,
  prescribed treatment course and duration
• Baseline viral load
• On-treatment viral response at 4 weeks
• Hepatic factors lever of fibrosis, etc.
• Age, gender, ethnicity

33
Common Factors That Predispose to Lower SVR With
PegIFNRBV

• Genotype 1
• High HCV RNA levels
• Cirrhosis/bridging fibrosis
• Steatosis on liver biopsy

• Aged 40 years or older
• Male gender
• Heavier body weight
• African American ethnicity
• Metabolic syndrome/insulin resistance
• Diabetes
• Immunosuppression
• Alcohol abuse

Patient Related
Disease Related

• Adherence
• Treatment duration and regimen
• Contraindications
• Dose reductions

Treatment Related
34
Goals of Treatment of Common Viral Infections

• HIV
• Suppression, maintenance
• HBV
• Suppression, maintenance
• HCV
• Cure !!

35
Cure- Achievable in HCV Infection ?? -

• Since HCV an RNA virus does not integrate into
  the host cells genome, most clinicians,
  practitioners and researchers believe that in
  most patients infected with HCV, the virus is
  capable of being cleared from all compartments of
  infection within the body

36
Current Standard of Care for HCV Infection

• Injectable Pegylated Interferon, in combination
  with
• Oral ribavirin

37
Sustained Viral Response Rates with PEG-IFN /RBV
76-82
42-46
Genotype 1
Genotype Non-1
Strader et al. Hepatology 391147-1171
38
Milestones Achieved, Miles to Go
1986
1998
2001
2002
54-56
SVR ()
42
39
34
16
6
PEG-IFN /RBV 12 m
IFN/RBV 12 m
IFN 6 m
IFN/RBV 6 m
IFN 12 m
PEG-IFN 12 m
Strader et al. Hepatology 391147-1171
39
Shortcoming of Current HCV Therapies

• Low sustained response, cure rates
• Side effects of both interferon and ribavirin
• Duration of therapy
• Costs
• Lack of understanding of mechanism of action

40
Interferons - Mechanism of Action in HCV -

• Direct antiviral activity
• Anti-proliferative effects
• Immunomodulatory effects

41
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Evolving Therapies for HCV

• New interferon derivatives
• Small molecule, orally active antivirals
• Specifically targeted anti-viral therapy for
  hepatitis C (STAT-C)
• Protease inhibitors
• Polymerase inhibitors
• Cyclophilin inhibitors
• Others
• Combination regimens

43
Albuferon HGS/Novartis
44
Albuferon plus RBV in Treatment NaïvesPhase
IIb Study Design
Zeuzem AASLD 2007
45
Albuferon for Naïve HCV Patients
Zeuzem AASLD 2007
46
Optimizing Adherence on Interferon- Educate,
Support -

• Encourage habits, activities that promote good
  health and well-being
• Observe, report s/sx of depression
• Importance of diet, exercise, rest
• Optimize hydration !!
• Evening, bedtime dosing generally better
  tolerated
• Ancillary medications as required
• Be There !!

47
Specifically Targeted Antiviral Therapy for
Hepatitis CSTAT-C
48
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50
Specifically Targeted Antiviral Therapies for HCV
(STAT-C)
Kwong et al. Drug Discovery Today Therapeutic
Strategies, Vol. 3, No. 2 2006
51
STAT-C- Protease and Polymerase Inhibition -
C
E1
E2
p7
NS2
NS3
NS4A
NS4B
NS5A
NS5B
Polymerase
Protease
Kwong et al. Drug Discovery Today Therapeutic
Strategies, Vol. 3, No. 2 2006
52
The protease cleaves the HCV polyprotein chain,
initiating replication
NS3/4A Protease
NS2
P7
NS4B
E2
NS5A
E1
NS5B
C
Kwong et al. Drug Discovery Today Therapeutic
Strategies, Vol. 3, No. 2 2006
53
Protease inhibitors prevents cleavage of the
polyprotein chain, preventing viral replication
Protease inhibitor binds to protease
Downstream cleavage is halted
Protease
Kwong et al. Drug Discovery Today Therapeutic
Strategies, Vol. 3, No. 2 2006
54
The final enzyme cleaved from the HCV
polyprotein, the polymerase is critical to RNA
replication
Replicated RNA
NS5B
HCV replicase
RNA template
Kwong et al. Drug Discovery Today Therapeutic
Strategies, Vol. 3, No. 2 2006
55
Inhibition of the polymerase halts viral
replication downstream
Polymerase inhibitor
NS5B
HCV replicase
RNA template
Kwong et al. Drug Discovery Today Therapeutic
Strategies, Vol. 3, No. 2 2006
56
STAT-C Agents in Development- Protease
Inhibitors -

• Agent Company Phase
• Telaprevir Vertex/JNJ III
• Boceprevir Schering II/III
• ITMN-191 Intermune/Roche I
• TMC-435350 Tibotec/Medivir I

57
TelaprevirPROVE Clinical Trials
58
PROVE-1 Study Design
Current Analysis
Arm A
75 Pts
EOT
79 Pts
Arm B
EOT
Follow-up
79 Pts
Arm C
SVR
Follow-up
Arm D
17 Pts
SVR
48
12
24
0
Weeks on Therapy
TVR/Peg-IFN/RBV
Peg-IFN/RBV

• Subjects in Arms C and D needed an RVR at week
  4, and had to remain HCV RNA undetectable
  through end of assigned dosing, to end treatment
  at Week 24 and 12

59
TVR Groups had Significantly Better Antiviral
Response at Weeks 4 and 12
100
90
80
70
TVR groups N 175
60
Percent Undetectable (lt 10 IU/mL)
50
Control N 75
40
30
20
10
0
Week 12 ITT
Week 4 ITT
60
Boceprevir PEG IFN/RBVPhase II SPRINT-1
Study, 12-Week DataTreatment-Naive Patients,
Genotype 1
PEG IFN PEG IFN ?-2b 1.5 µg/kg/wkRBV
8001400 mg/dBoc boceprevir 800 mg
TIDLow-dose RBV 4001000 mg/d
100
79
8
0
70
54
6
0
HCV RNA Undetectable
34
4
0
2
0
0
PEG IFN RBV,48 wk
Boc PEG IFN RBV,24 or 48 wk
PEG IFN RBV for4 wk, then Boc added for 24 or
44 wk
Boc PEG IFN low-dose RBV,48 wk
Schering-Plough CorporationGraphic courtesy of
Dr. Ira Jacobson.
61
STAT-C Agents in Development- Polymerase
Inhibitors -

• Agent Company Phase
• R-1626 Roche II
• R-7128 Pharmasset/Roche IIa
• GS-9190 Gilead I
• MK-0608 Merck I
• BILB-1941 Boehringer-Ingelheim I
• A-837093 Abbott I

62
GS-9190
63
Antiviral, Pharmacokinetic and Safety Data for
GS-9190, a Non-nucleoside HCV NS5B Polymerase
Inhibitor, in a Phase I Trial in HCV Genotype 1
Infected Patients

• Bavisotto L, Wang C, Jacobson I, Marcellin P
  Zeuzem S, Lawitz E, Lunde NM, Sereni P, OBrien
  C, Oldach D, Rhodes G the GS-9190 Study Team. 

64
GS-US-196-0101 Part B (Multiple Dose)Mean
Change from Pre-Dose in Log10 HCV RNA
-0.05
-0.20
-0.35
Cohort 1 (40mg)
-0.50
Cohort 2 (120mg)
-0.65
Placebo
-0.80
Change from Baseline HCV RNA Log10
copies/mL
Change from Baseline HCV RNA Log10
copies/mL
-0.95
-1.4 log10
-1.10
-1.25
-1.40
-1.55
-1.7 log10
-1.70
-1.85
-2.00
-2.15
-2.15
0
1
2
3
4
5
6
7
8
9
10
0
1
2
3
4
5
6
7
8
9
10
Time (days)
Part B Mean (SE)
Time (days)
Part B Mean (SE)
65
STAT-C Agents in Development- Cyclophilin
Inhibitors -

• Agent Company Phase
• Debio-025 DebioPharm II
• NIM-811 Novartis I

66
Potential Pitfalls of STAT-C

• Emergence of Resistance
• Side effects
• When to use and with what

67
STAT-C Agents in Development
Thompson et al J Hepatology 2009 50184-94
68
The Future Of HCV Therapy
Viral enzyme inhibitors
Immune modulation
Ribavirin or related drugs


Interferon as a platform for future combinations
69
Management of HCV Infection- Moving Forward -

• Pegylated interferon Ribavirin or newer
  analogues likely to remain foundation of therapy
• Much RD interest ongoing to develop orally
  active, safe and effective small molecule
  antivirals
• Telaprevir and/or boceprevir MAY be approved in
  2011
• Combination therapy, similar to that used in HIV
  or HBV, is likely to evolve as standard of care
• Great opportunity exists to educate and support
  HCV patients in terms of regimen adherence,
  lifestyle modification, safe living, behaviors
  that promote good individual and public health

70
The Future of HCV Genotype 1 Therapy - The Next
Decade -
Thompson et al J Hepatology 200950184-94
71
Acknowledgements
72

• Hepatitis C is one of the most significant
  preventable and treatable public health problems
  facing our nation. a graver threat than the AIDS
  crisis.

73

• Hepatitis C is one of the most significant
  preventable and treatable public health problems
  facing our nation. a graver threat than the AIDS
  crisis.
• Surgeon General Dr. C. Everett Koop, 1998

74
Self-Assessment Questions
75
The primary age group infected with HCV in the
US is

• Infants born to HCV mothers
• Adolescents, 14-18 years of age
• Adults, 35-55 years of age

76
Risk of becoming infected from a percutaneous
exposure to an HCV individual

• A. 0.3
• B. 3.0
• C. 30.0

77
The current standard of care for chronic HCV
infection is

• Recombinant SC interferon
• Pegylated SC interferon oral Ribavirin
• Tenofovir Emtricitabine
• D. Telaprevir Peg-Interferon/Ribavirin

78
The key dose-limiting toxicity of Ribavirin

• Pancytopenia
• Stevens-Johnson syndrome
• Hemolytic anemia
• Teratogenicity

79
The first orally active, small molecule antiviral
likely to be approved for HCV is

• Elvitegravir
• Telaprevir
• Silibinin
• Nitazoxanide

80
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81
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82
Progression to Cirrhosis in HCV
Poynard et al J Hepatology 38 257-65
83
Worse QoL With Standard IFN RBV vs Peg-IFN

• 412 HCV-infected pts randomized to open-label
  treatment with peg-IFN alfa-2a without RBV vs IFN
  alfa-2b RBV

Standard IFN alfa-2b RBV
PegIFN alfa-2a
Mental Component Score
Physical Component Score
Week 4
Week 12
Week 4
Week 12
0
0
2
2
-1.5
-2.4
-3.1
Change in SF-36 Score From Baseline
Change in SF-36 Score From Baseline
4
4
-3.5
-3.9
-5.1
6
6
-5.9
-6.2
P .01
P .05
8
8
P .05
P .01
10
10
Perrillo R, et al. J Viral Hepat. 200411157-165.
84
Strategies to Manage On-Treatment AEs and QoL
Reductions

• IFN or RBV dose reductions indicated in certain
  circumstances1
• Epoetin alfa may allow RBV dose maintenance and
  QoL improvements2
• Specific AEs
• Flu-like symptoms plenty of liquids, warm soaks,
  mild exercise2
• Nausea, vomiting small frequent meals,
  electrolyte replacement, selective 5-HT3 receptor
  antagonists (ondansetron), antiemetics,
  antihistamines, antidopaminergic agents2
• Depression supportive psychotherapy, regulation
  of sleep, antidepressants
• Rash cool soaks with oatmeal products,
  moisturizers, oral antihistamines, low-dose
  hydrocortisone lotion, dermatology referral
• Alopecia decrease friction, decrease manual
  manipulation of hair, commercial products that
  improve appearance of thinning hair, wigs

1. Yee HS, et al. Am J Gastroenterol.
20061012360-2378. 2. Afdhal NH, et al.
Gastroenterology. 20041261302-1311.
85
Risk Factors for HCV InfectionUS, 2006
HCV is the most common blood-borne infection in
the US
IDUintravenous drug use.Wasley A, et al. MMWR
Surveill Summ. 200857(2)1-24
86
Gauging Treatment Results

• Sustained viral response SVR
• Undetectable virus in the blood six months after
  stopping treatment independent of treatment type
  
• SVR Cure ??

87
Albuferon for Naïve HCV Patients
Zeuzem AASLD 2007
88
Nitazoxanide (Alinia)
Cryptosporidium parvum
Giardia lamblia
89
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90
STAT-C Agents in Development
Thompson et al J Hepatology 2009 50184-94
91
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