Hepatitis C Choices in Care HCV State of the Art Management for a Curable Disease Robert G. Gish MD Robert G Gish Consultants LLC Member VHAC Founding.

Hepatitis C Choices in Care

HCV State of the Art Management for a Curable Disease

Robert G. Gish MDRobert G Gish Consultants LLCMember VHACFounding member of CEVHAPExecutive Committee (VP): NVHRSenior Medical Director: St Josephs Medical Center PhoenixProfessor of Clinical Medicine University of Nevada Las Vegas

Future

After HEPTIC EMR

program

Complexity of Hepatitis C Patient Management

Why Treat Chronic Hepatitis C? The disease

Common, chronic, and potentially progressive Complications are becoming more common

Liver failure Hepatocellular carcinoma (HCC)

Decrease transmission Improve quality of life Systemic disease Improve survival due to the linkage of HCV to (non liver) all cause

mortality Decrease immediate and long-term health care costs

The treatment Viral cure, or sustained virologic response (SVR), is achievable SVR associated with histologic improvement and gradual regression of

fibrosis1

SVR leads to lower risk for liver failure and HCC, and improved survival2,3

1. Poynard T, et al. Gastroenterology. 2002;122:1303-1313. 2. Craxi A, et al. Clin Liver Dis. 2005;9:329-346. 3. Shiratori Y, et al. Ann Intern Med. 2005;142:105-114.

Treatment starts NOW with behavior modification Alcohol abstinence Weight loss of OW/Obese No THC use Stop IVDU

HCV as a Systemic Disease

Association between chronic HCV infection and: Diabetes/insulin resistance Cardiovascular disease HCV and Brain: decreased cognitive function and QOL Cancer Renal impairment

Effects of antiviral therapy and SVR on prognosis: Clear mixed cryoglobulinemia Decrease liver-related mortality Abrogate non-liver-related mortality Stop graft loss in renal and liver transplant patients Change outcomes in immune suppressed patients with HIV

and other treatments or disease states

SVR Reduces Risk of Development of Diabetes in Patients with HCV

Veterans Affairs Clinical Case Registry: 27,636 patients with HCV

Followed for median 5 years Antiviral treatment initiated 1998-2007

Hyder S et al. DDW 2013; poster 608.

Hyder S. and et al Digestive Disease week, 2013

HR = 0.77: 95% CI 0.71-0.84

HCV+ individuals die 15 years sooner

Pinchoff J et al. IDWeek 2013; poster 1777.

CHeCS: Annual Rate of Length of Stay (days/year) by FIB4 score*, 2006-2010

2006 2007 2008 2009 20100

1

2

3

4

5

6

7

8

9

10

FIB4<=1.21

1.21<FIB4<=5.88

FIB4>5.88

Year

LOS

rate

(day

/per

son-

year

)

*FIB4, calculated from ALT, AST, platelet count and patient age, increases with worsening fibrosis; values > 5.88 indicate cirrhosis and end-stage liver disease

HCV-infected persons in CHeCS:Mortality rates also increasing* Year

Mortality rate (per 100 py)

2006 1.4

2007 2.1

2008 2.8

2009 3.2

2010 4.4

From: R Mahajan et al, Abstract submitted to IDWeek 2013

The real impact of HCV mortality in the United States* Despite high death rates, only 19% of the 1600 confirmed chronic

HCV patients in CHeCS had HCV infection noted on their death certificate; only 30% even of those dying with liver-related conditions

70% had pre-mortem ICD9 codes, liver biopsies, and FIB4 scores indicative of substantial liver damage

This suggests that even if all HCV-infected patients are identified before death– clearly, not the case-- actual mortality in them exceeds 80 000/yr, most of it contributed to by underlying HCV-related liver disease

Whatever the listed cause of disease, HCV-infected persons died 15 years younger than everyone else

*Reena Mahajan et al, ‘Rates and Causes of Mortality…”, Manuscript submitted; IDWeek 2013 abstr 1774

Current Treatment

The Evolution of HCV Therapy

Strader DB, et al. Hepatology 2004;39:1147-71.

Series10

20

40

60

80

100

SV

R (

%)

IFN6 mo

IFN/RBV6 mo

PEG-IFN /RBV

12 mo

IFN12 mo

IFN/RBV12 mo

PEG-IFN12 mo

1986 1998 2001 2002

6

16

34

42 39

54-56

70-75

PEG-IFN /RBV + PI6-12 mo

2011-13 2014+

90+%+/-INF

RIBA

Side Effects

PEG IFN/RBV + new therapies results in increased SVR rates, this may be accompanied by a higher incidence of

Anemia, often requiring erythropoietin and/or transfusion Rash Taste abnormalities (dysgeusia) Fatigue Flu-like symptoms Nausea Pruritus/dry skin Neutropenia/thrombocytopenia Fever Depression +++

Poordad F, et al. N Engl J Med. 2011;364:1196-1206. Bacon BR, et al. N Engl J Med. 2011;364:1207-1217.Sherman KE, et al. 61st AASLD; October 29-November 2, 2010; Boston, Mass. Abstract LB-2.Telaprevir NDA 201-917. April 28, 2011. Available at: www.fda.gov.

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

Telaprevir n = 295

Serious adverse events (SAEs)* 535 in 160 patients (54.2%)

Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%)

Death 7 (2.4 %)

Infection (Grade 3/4)† 27 (9.1 %)

Hepatic decompensation (Grade 3/4) 15 (5.1 %)

Rash (grade 3/SCAR) 16 (5.4 %) / 2 (0.6 %)

Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9 %)

EPO use / blood transfusion 168 (57 %) / 53 (18 %)

GCSF use 8 (2.7 %)

TPO use 6 (2 %)*SAEs in patients; SCAR: severe cutaneous adverse reaction†3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy, 1 pulmonary neoplasia, 1 pulmonary infection

INF + Riba +Telaprevir: SVR12 safety findings

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

Boceprevir n = 190

Serious adverse events (SAEs)* 321 in 97 patients (51.0%)

Premature discontinuation / due to SAEs 80 (42.1%) / 27 (14.2%)

Death† 3 (1.6 %)

Infection (Grade 3/4) 8 (4.2 %)

Hepatic decompensation (Grade 3/4) 9 (4.7 %)

Rash (grade 3/SCAR) 2 (1.0 %)

Anemia (Grade 3/4: Hb < 8 g/dL) 19 (10.0 %)

EPO use / blood transfusion 119 (62.6 %) / 26 (13.7 %)

GCSF use 13 (6.8 %)

TPO use 3 (1.6 %)*SAEs in patients; SCAR: severe cutaneous adverse reaction†1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia

INF + Riba + Boceprevir: SVR12 safety findings

Antiviral activity in all HCV genotypes

No/less selection of resistance

All-oral combination regimenShort treatment

duration 6-12 weeks

QD (or BID) dosingExcellent safety and tolerability

Less or no DDI

Applicable in difficult-to-treat populations: Transplant Coinfection End-stage renal disease, etc.

HCV — The Revolution Has Begun

1990 2000 2005 2010 2011 2012 2013 2014 2015

Interferon

Ribavirin

Pegylatedinterferons

Proof of concept for

DAA (PI)

Suppression of HCV with DAA combination

(PI + NI)

Telaprevir and

boceprevir

Curability of HCV without

InterferonTarget >90% SVR reached in Phase

II and III trials

Frequent curability of

diverse populations without IFN

Approval of simeprevir and sofosbuvir with IFN:G1, others?First approved

IFN-free therapy: SOF+RBV: G2, 3

IFN-free DAAcombinations (G1) SVR 90-100%

Potential approval of other DAAs

with IFN(eg faldaprevir)

HCV Therapy—Past, Present, and Future

Thank you to Dr Ira Jacobson

Two New Protease Inhibitors are coming in combination with PEG IFN/RBV

Simeprevir NS3 protease Inhibitor Q daily dosing Improved side effect profile No anemia Fewer DDIs

Faldaprevir NS Protease

inhibitor Q daily dosing Improved side

effect profile No anemia

18

Simeprevir (TMC 435)

HCV-specific NS3/4A protease inhibitor Antiviral activity in patients infected with

GT 1, 2, 4, 5, and 6 Oral, once-daily tablet Limited drug-drug interactions as CYP 3A4

inhibitor only at level of intestine Safe and well tolerated, n ~3800 patients

Simeprevir—Completed Phase III Studies

QUEST-1 and QUEST-2 Same study design, but conducted

independently of each other

Treatment-naïve GT 1 patients

PROMISE Same study design as QUEST-1 and QUEST-2 GT 1 prior relapsers

Jacobson I, et al. EASL 2013, Abstract 1425. Manns M, et al. EASL 2013, Abstract 1413. Lawitz E, et al. DDW 2013, Abstract 869b.

QUEST-1 QUEST-2 PROMISE0

20

40

60

80

100

Simeprevir/PEG/RBV PEG/RBV

SV

R1

2 (

%)

Simeprevir + PEG/RBV Achieved SVR in ~80% of Treatment-Naïve and Prior Relapsers

210/264

65/130

206/260

209/257

67/134

49/133

80*

50

81*

50

79*

37

*P<0.001Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013;Abstract 869b.

QUEST-1—SVR by Subgroup

Jacobson I, et al. EASL 2013;Abstract 1425.

Fibrosis Genotype IL28B genotype

Q80K polymorphism affected SVR

F0-F2 F3-F4 1a 1b/other CC CT TT0

20

40

60

80

100

SIM+PR PR

SV

R1

2 (

%)

8390

60

70

28

71

49 52

94

78 76

42

65

24

152/183

54/90 54/77 11/40 105/147

36/74 105/117

29/56 72/77 29/37 114/150

32/76 24/37 4/17

QUEST-2—SVR by Stage of Fibrosis

Jacobson I, et al. EASL 2013;Abstract 1425. Manns M, et al. EASL 2013;Abstract 1413. Lawitz E, et al. DDW 2013; Abstract 869b.

F0-F2 F3 F4 (Cirrhosis)0

20

40

60

80

100

Simeprevir/PEG/RBV + PR PEG/RBV

SV

R1

2 (

%)

85

67

53

65

51

40

165/195 52/102 24/36 9/17 11/17 6/15

ASPIRE—Virologic Response to Simeprevir + PEG/RBV in Prior Partial and Null Responders

SMV 100 mg* + PEG/RBV SMV 150 mg* + PEG/RBVPlacebo + PEG/RBV

*For each dose, SVR for different treatment durations were similar so results were pooled.Abbreviation: SMV, simeprevir.

Zeuzem S, et al. EASL 2012;Abstract 2.

80

SV

R24

(%

)

0

40

60

20

Relapsers Partial Responders Null Responders

37

85 85

9

57

75

19

4651

27 79 79 23 68 69 16 50 51n =

100

QUEST-2—Safety Profile

Adverse Events SMV/PR

(n = 257)Placebo/PR (n = 134)

Grade 1 or 2 AE 70.0 73.1Grade 3 or 4 AE 25.7 23.9Serious AE 2.3 1.5AE leading to discontinuation of SMV* 1.6 0.7Most common AEs (≥25% in SMV arm)

Headache 37.0 33.6Pyrexia 30.4 35.8Fatigue 34.6 38.8Influenza-like illness 25.7 25.4

Other AEs of interestRash (any type) 23.7 11.2Anemia 13.6 15.7Pruritus 18.7 14.9Photosensitivity conditions 3.9 0.7· Data for the first 12 weeks of treatment are shown

· The majority of rash AEs in the SMV/PR group (97.0%) were grade 1 or 2

*Without regard to PEG IFN and RBV.Abbreviations: AE, adverse event; PR, PEG IFN + ribavirin; SMV, simeprevir.

Manns M, et al. EASL 2013;Abstract 1413.

Patient %

Simeprevir—Benefits

Virtually all patients qualify for short-duration (24 weeks) therapy

Limited drug-drug interactions

Daily dosing

Simeprevir—Data Gaps

GT 2 and 4 subtypes

Phase III data in prior PEG/RBV partial and null responders

Renal disease

Pre and post transplant

All Oral: Sofosbuvir plus RibavirinGenotype 2 and 3*

81

97 100

50

87

98 100

73

0

20

40

60

80

100

2 4 EOT SVR

% H

CV

RN

A (

-)

Treatment Week

12

16

Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.

Weeks ofTreatment:

(N=100)

(N=95)

*Patients with previous non-response to IFN-based treatment

All Oral: Sofosbuvir plus RibavirinCirrhosis vs No Cirrhosis

No Cx Cx No Cx Cx0

20

40

60

80

100 96

60

37

19

100

78

63 61

12

16

SV

R (

%)

Jacobson IM, et al. . N Engl J Med 2013;368:1867-77.

Weeks ofTreatment:

Genotype 3Genotype 2

(N=100)

(N=95)

25/26

23/23

6/10

7/9

14/38

25/40

5/26

14/23

Sofosbuvir + RBVVALENCE: Genotype 2,3 IFN naïve, ineligible or treatment failures

SOF+RBV (n=73)

SOF+RBV (n=250)

SVR12 =93% G2

G3

Series10

102030405060708090

100Genotype 3

93 9285

60

Naïve Treatment-experienced

Noncirrhotic Cirrhotic Noncirrhotic Cirrhotic

SVR 12 (%)

86/92 12/13 85/100 27/45

FDA Advisory Committee Meeting, Oct 25, 2013; Zeuzem S et al, AASLD 2013, #1085

Wk 0 Wk 24

Sofosbuvir/PegIFN/RibavirinGenotype 1 (N=327)

9199 99

90

0

20

40

60

80

100

2 4 EOT SVR

% H

CV

RN

A (

-)

Treatment Week

Lawitz E, et al. N Engl J Med 2013;368:1878-87.

SMV/ SOF12 Wks

SMV/ SOF/RBV12 Wks

0102030405060708090

100

92 96

7.83.7

24 week treatment

13/14 26/27

SMV/SOF12 wks

SMV/SOF/RBV12 wks

SVR12 (SMV/SOF)

SVR12 (SMV/SOF/RBV)

1/271/14

0102030405060708090

100

100 79

16.7

4.2

14/14 19/24

SMV/SOF24 wks

SMV/SOF/RBV 24 wks

Pat

ien

ts (

%)

1/24

4/24

Non-virologic failure

Relapse

Cohort 1: Null responders (F0-2)

12 week treatment

Total Naives Nulls0

102030405060708090

100100 100 10096.3 100

93.3

Pat

ien

ts (

%)

1/27

SVR4 (SMV/SOF)

SVR4 (SMV/SOF/RBV)

12 week treatment

7/7 12/12 7/7 14/15

1/15

Relapse

26/2714/14

Cohort 2: Naïve and prior null responders (F3-4): Interim analysis, SVR4

9 naïve and 9 null responders METAVIR F4 patientsOnly relapser was a F4 prior null responder

Conclusion

Treatment with SMV + SOF ± RBV results in: High SVR12 rates in HCV GT 1 null responder patients High SVR4 rates in naïve and null-responder patients

with METAVIR F3-F4 These findings suggest that addition of RBV to

SMV + SOF may not be necessary to achieve good virologic response in this patient population

12 weeks’ treatment may confer similar clinical benefit to 24 weeks’ treatment

SMV + SOF ± RBV was generally well tolerated

IFN-free SummaryCross-company Studies

Weeks SVR

Daclatasvir + Sofosbuvir (N=41, GT-1)

12 100%

Simeprevir + Sofosbuvir COSMOS (N=80)

12 100%

Sulkowski MS, et al. EASL 2013; abstract 1417.Lawitz EM, et al. CROI 2013; abstract 155LB.

IFN-free SummaryPhase 2 Study Results

Weeks SVR

ABT450/r + ABT267 + ABT333 + RBV (N=571)

12 ~90%

Sofosbuvir + ledipasvir + RBV (N=34) 8-12 95-100%

Faldaprevir + deleobuvir + RBV (GT1b, N=20)

16 ~95%

DCV + ASV + BMS-791325 (N=66) 12-24 88-94%

Kowdley K, et al. EASL 2013; abstract 3.Gane E, et al. CROI 2013; abstract 41LB.Zeuzem S, et al., APASL 2013.Everson GT, et al. IDSA 2013; abstract 1828.

2013 2014 2015 2016

Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4

2013 2014 2015 2016

Projected Timing for New Regimen Launches

Sofosbuvir + RBV

GT2/3, Naïve/Tx-EXP/

IFN Ineligible TX-Exp

BMS DCV/ASV/RBV*

-----GT1b Naïve/Tx-

Exp/IFN IntolerantDaclatasvir

Triple-----

Gt1. Naïve onlySofosbuvir +

lepedisvir-----

GT1/2/3, Naïve/TX-EXP/

IFN Ineligible

ABT-450/267/333/RBV

----GT1, Naïve/Tx-EXP

Faldaprevir(BI201335) Triple

----GT1 Naïve, Tx-EXP

Sofosbuvir Triple----

GT1, 4, 5, 6, Naive

Simeprevir Triple----

GT1, Naïve, Tx-Exp

TripleIFN-Free

* Precise timing TBD

COSMOS StudyOff Label use

SOF + SIM G-1

To Treat or not to Treat:

A Constellation of Considerations

Duration ofinfection

Personal plans(marriage,

pregnancy)Age

COST

HIV coinfectionExtrahepatic

Features(Fatigue, EMC, PCT)

Patient"mindset"

Genotype virusGenotype Patient (IL28)

Q80K mutation or others

Contraindications& comorbidities

Insulin Resistance

Histologic stage20%+ life time risk

Of cirrhosis

Family and othersupport

Occupation

To Treat or not to Treat:A Constellation of Considerations