CADTH SYMPOSIUM : HCV:

NATURAL HISTORY AND THERAPEUTICS

Alnoor RamjiGastroenterology & HepatologyClinical Associate ProfessorDivision of GastroenterologyUniversity Of British ColumbiaSt. Paul’s Hospital Siteramji_a@hotmail.com

Company Name Relationship

Abbvie Investigator, consultant

BI Investigator, Consultant

BMS Investigator, Consultant, Speaker

Gilead Sci. Inc Investigator, Consultant, Speaker

Hoffman LaRoche Investigator, Consultant, SpeakerNursing Support

Janssen (J. & J.) Investigator, Consultant, Speaker

Novartis Investigator

Merck & Co. Investigator, Consultant, SpeakerNursing Support

Vertex Pharmaceuticals Investigator, Consultant, Speaker

Disclosures

Objectives

• Review the natural history of hepatitis C and its complications.

• Understand Treatment options for hepatitis C– Pegylated-interferon + ribavirin +/- Direct acting

anti-virals (DAA’s).

– Combination DAA’s

1a, 1b 2a, 2b,

3a

1a, 1b 2a, 2b,

2c, 3a

4

5a

1b

1b, 6

1b, 3a

1b, 3a

3b

4

Fang et al. Clin Liver Dis. 1997.

HCV Infection: Worldwide Genotype Distribution

1a, 1b, 2b, 3a

2a

5HCC: hepatocellular carcinoma.1. Alter and Seeff. Semin Liver Dis. 2000;20:17-35; 2. Pinette et al. Public Health Agency of Canada. Available from: http://www.phac-aspc.gc.ca/hepc/pubs/pdf/hepc_guide eng.pdf; 3.Myers et al. Can Gastroenterol. 2012;26:359-75.

Projection of Lifetime Outcomes1

100 patients with acute HCV infections

100 patients with acute HCV infections

24 patientschronic, nonprogressive

24 patientschronic, nonprogressive

24 patientssevere progressive hepatitis

24 patientssevere progressive hepatitis

32 patientsvariable progression

32 patientsvariable progression

20 patients recover20 patients recover 80 patientspersistent infection

80 patientspersistent infection

All patients should seek antiviral therapy2,3All patients should seek antiviral therapy2,3

End-stage disease, HCC, liver transplantation,

death

End-stage disease, HCC, liver transplantation,

death

Treatment failureTreatment failureSustained response/cureSustained response/cure

Outcomes:Outcomes:

Disease Progression and Morbidities

6Pre-Submission Briefing Meeting | July 2014 | Company Confidential © 2014 AbbVie

1. O’Leary 2008; 2. Perz 2006; 3. White 2008

Disease progression in patients with chronic HCV

Morbidities associated with chronic HCV infection1,2

•Cirrhosis•Decompensated cirrhosis: Ascites, varices, Encephalopathy•Hepatocellular carcinoma (HCC)

• 312 patients with initially compensated cirrhosis of viral aetiology

Cirrhotic patients at risk of serious morbidity

Benvegnù L, et al. Gut 2013; 53: 744‒9

Patients at riskHCC 312 311 310 303 297 268 226 189 153 129 94 65 45 27 11 5

Variceal bleeding 312 312 312 309 301 269 237 190 163 131 97 71 44 29 13 7

Ascites 312 311 312 305 296 259 223 181 152 125 93 60 48 30 15 9

Encephalopathy 312 312 312 309 300 270 235 192 161 127 95 65 43 30 13 7

Cu

mu

lati

ve r

isk

(%)

Years of follow-up

HCCVariceal bleedingAscitesPortal-systemic encephalopathy

50

40

30

20

10

00 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15

Variceal Hemorhage

Adapted from the US Food and Drug Administration, Antiviral Drugs Advisory Committee Meeting, April 27-28, 2011, Silver Spring, MD.

SV

R (

%)

IFN6 mos

PegIFN/ RBV 12 mos

IFN12 mos

IFN/RBV12 mos

PegIFN12 mos

2001

1998

2011

StandardIFN

RBV

PegIFN

1991

DAAs

PegIFN/RBV/DAA

IFN/RBV6 mos

6

16

3442 39

55

70+

0

20

40

60

80

100

The Advancing Present

2014/590-98

PegIFN/RBV/DAAOr DAA+RBV

Viral Eradication Improves All-Cause Mortality

10References: 1. Ravazi 2012; 2. Burra 2009; 3. Guillouche 2011; 4. Van der Meer 2012

• Cure = SVR = reduced risk of — All-cause mortality; Liver-related mortality; HCV-related complications:-

Progression to HCC or liver failure4

Pat

ien

t su

rviv

al o

utc

om

es

wit

h a

nd

wit

ho

ut

SV

R

Pre-Submission Briefing Meeting | July 2014 | Company Confidential © 2014 AbbVie

HCV Lifecycle and DAA Targets

Adapted from Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

Receptor bindingand endocytosis

Fusion and

uncoating

Transportand release

(+) RNA

Translation andpolyprotein processing

RNA replication

Virionassembly

Membranousweb

ER lumen

LD

LDER lumen

LD

NS3/4 protease inhibitors

NS5B polymerase inhibitors

*Role in HCV lifecycle not well defined

NS5A* inhibitors

0

20

40

60

80

100S

VR

(%

)

PegIFN/RBVBOC or TVR + PegIFN/RBV

38-44

67-81

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

2012 – 2014: SVR Rates: Boceprevir or Telaprevir with PEG-INF + Ribavirin in Genotype 1 Treatment-Naive

Patients: upto 48 Weeks

F0-2 F3-4

52-62

Boceprevir Triple therapy Safety Profile 48 PR

n=363

BOC RGT

n=368

BOC/PR48

n=366

Median treatment duration, days 203 197 335

Deaths N=4 N=1 N=1

Serious AEs 9% 11% 12%

Discontinued due to AEs 16% 12% 16%

Dose modification due to AEs 26% 40% 35%

Hematologic parameters

Neutrophil count (<750 to 500/mm3 / <500/mm3)

14% / 4% 24% / 6% 25% / 8%

Hemoglobin (<10 to 8.5 g/dL / <8.5 g/dL)

Discontinuation due to anemia

Dose reductions due to anemia

Erythropoietin use

Mean (median) days of use

26% / 4%

1%

13%

24%

121 (109)

45% / 5%

2%

20%

43%

94 (85)

41% / 9%

2%

21%

43%

156 (149)

Adverse Event Arm 1 (PR48); n=363 (%) Arm 2 (RGT); n=368 (%) Arm 3 (BOC/PR48); n=366 (%)

Fatigue 59 52 57

Headache 42 45 43

Nausea 40 46 42

Anemia 29 49 49

Dysgeusia 18 37 43

Chills 28 36 33

Pyrexia 32 33 30

Insomnia 32 31 32

Alopecia 27 20 28

Decreased Appetite 25 26 24

Pruritis 26 23 25

Neutropenia 21 25 25

Influenza Like Illness 25 23 22

Myalgia 26 21 24

Rash 22 24 23

Irritability 24 22 22

Depression 21 23 19

Diarrhea 19 19 23

Dry Skin 18 18 22

Dyspnea 16 18 22

Dizziness 15 21 17

Boceprevir Triple: Common Treatment-Related Adverse Events*

*Reported in >20% of patients in any treatment arm and listed by decreasing overall frequency

0

20

40

60

80

100S

VR

(%

)

Simeprevir

85%

90%

2014 /2015 :Virologic Response to PEG-INF + RBV + Simeprevir or Sofosbuvir in Genotype 1

Treatment-Naive Patients

80%

CirrhosisNoCirrhosis

60%

Sofosbuvir

CirrhosisNo Cirrhosis

Jacobson I, et al. EASL 2013. Abstract 1425. Reproduced with permission.Lawitz E, et al. EASL 2013. Abstract 1411. Reproduced with permission.

0

20

40

60

80

100S

VR

(%

)

SOF/ LDV +/-RBV x 8-12 wks

97-100% 93-100%

Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12Poordad F, et al. EASL 2014. Abstract O163

2015 /2016 :Virologic Response to Non-interferon based therapy: Genotype 1 :Treatment-Naive Patients:

Non-cirrhotic and cirrhotic sub-groups

ABT 450/rtv + ombitasvir + dasabuvir+RBVX 12 wks

0

20

40

60

80

100S

VR

(%

)

SOF/ LDV +/-RBV 12-24 wks

82-100% 93-100%

2015 /2016 :SVR to Non-interferon based therapy: Geno. 1 :Treatment Experienced Patients:

Non-cirrhotic and cirrhotic sub-groups

ABT 450/rtv + ombitasvir + dasabuvir+RBVX 12 -24 wks

Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

AEs

SAPPHIRE I SAPPHIRE II

3 DAA + RBV(n = 473)

Placebo(n = 158)

3 DAA + RBV(n = 297)

Placebo(n = 97)

Any AE, n (%) 414 (87.5) 116 (73.4) 271 (91.2) 80 (82.5)

AE leading to D/C, n (%) 3 (0.6) 1 (0.6) 3 (1.0) 0

Any serious AE, n (%) 10 (2.1) 0 6 (2.0) 1 (1.0)

Grade 3/4 lab events, n/N (%)

ALT 4/469 (0.9) 7/158 (4.4) 5/296 (1.7) 3/96 (3.1)

AST 3/469 (0.6) 3/158 (1.9) 3/296 (1.0) 1/96 (1.0)

Alkaline phosphatase 0 0 0 0

Creatinine – – 2/297 (0.7) 0

Total bilirubin 13/469 (2.8) 0 7/296 (2.4) 0

Hemoglobin < 8 g/dL 0 0 1/296 (0.3) 0

Hemoglobin < 10 to 8 g/dL, % 5.8 0 4.7 0

Feld JJ, et al. N Engl J Med. 2014;370:1594-1603. Zeuzem S, et al. N Engl J Med. 2014;370:1604-1614.

ABT 450/rtv + ombitasvir + dasabuvir+RBV(Holkira) with RBV in Non-cirrhotic GT1 Pts: Tolerance

compared to placebo

Younossi ZM, AASLD, 2014, Poster #1445

Treatment with LDV/SOF (Harvoni) Improves PROs in CHC Patients with Early as well as Advanced Hepatic Fibrosis

0

20

40

60

80

100S

VR

(%

)

PegIFN/RBVX 24 wks

70-80%

97%

Poordad F, et al. N Engl J Med. 2011;364:1195-1206. Jacobson IM, et al. N Engl J Med. 2011;364:2405-2416.

2014 /2015 :Virologic Response to PEG-INF + RBV vs. Sofosbuvir + RBV (all-oral) in Genotype 2 and 3

Treatment-Naive Patients

Geno 2SOF+RBVX 12 wks

92-94%

Geno 3SOF+RBVX 24 wks

Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

LDV/SOF (Harvoni) + RBV for HCV Patients with Decompensated Cirrhosis: SVR-12

SOLAR-1: LDV/SOF + RBV in Decompensated Cirrhosis

CTP B CTP C

SV

R12

(%

)

26/30 19/22 18/2024/27

Error bars represent 90% confidence intervals.

LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks

SVR rates were similar with 12 or 24 weeks of LDV/SOF + RBV

Flamm, AASLD, 2014, Oral #239

Ascites Hepatic Encephalopathy

Patients, nSOF + RBV

n=25Observation

n=25SOF + RBV

n=25Observation

n=25

Baseline 6 9 5 2

Week 12 5 8 3 3

Week 24 0 7 0 4

Cirrhosis and Portal Hypertension Study (SOF+RBV)

Platelets (103/µL) Albumin (g/dL)

SOF+RBV Observation 24 weeks

ALT (U/L)

CTP A CTP B

Afdhal N, EASL, 2014, O68

p=0.003

p=NS

p=0.001 p=0.001

‡SOF+RBV for Treatment of Chronic HCV with Cirrhosis

and Portal HTN ± Decompensation: Week 24 Interim Results

Hepatitis C: Summary

• HCV has a slowly progressive course to cirrhosis, with complications of decompensated disease.

• Newer regimen: all-oral, efficacious, well tolerated

• Viral eradication / cure in 70-98%

• Viral eradication has a mortality benefit

CADTH SYMPOSIUM : HCV:

NATURAL HISTORY AND THERAPEUTICS

Alnoor RamjiGastroenterology & HepatologyClinical Associate ProfessorDivision of GastroenterologyUniversity Of British ColumbiaSt. Paul’s Hospital Siteramji_a@hotmail.com